U.S. patent number 6,235,747 [Application Number 08/816,235] was granted by the patent office on 2001-05-22 for 6-phenyl-pyridin-2-ylamine derivatives.
This patent grant is currently assigned to Pfizer Inc.. Invention is credited to John A. Lowe, III, Peter J. Whittle.
United States Patent |
6,235,747 |
Lowe, III , et al. |
May 22, 2001 |
6-phenyl-pyridin-2-ylamine derivatives
Abstract
The present invention relates to certain
6-phenyl-pyridin-2-ylamine derivatives that exhibit activity as
nitric oxide synthase (NOS) inhibitors, to pharmaceutical
compositions containing them and to their use in the treatment and
prevention of central nervous system disorders.
Inventors: |
Lowe, III; John A. (Stonington,
CT), Whittle; Peter J. (Sandwich, GB) |
Assignee: |
Pfizer Inc. (New York,
NY)
|
Family
ID: |
21764907 |
Appl.
No.: |
08/816,235 |
Filed: |
March 13, 1997 |
Current U.S.
Class: |
514/278; 514/183;
514/339; 546/276.7; 546/20; 546/16; 546/125; 546/112; 544/105;
540/582; 540/477; 540/349; 514/304; 514/216; 514/230.5; 514/249;
514/299 |
Current CPC
Class: |
A61P
9/00 (20180101); A61P 27/00 (20180101); C07D
405/12 (20130101); A61P 11/00 (20180101); C07D
451/04 (20130101); A61P 15/00 (20180101); A61P
19/00 (20180101); A61P 29/00 (20180101); A61P
15/08 (20180101); C07D 401/10 (20130101); C07D
417/12 (20130101); A61P 27/06 (20180101); A61P
25/30 (20180101); C07D 409/12 (20130101); A61P
25/26 (20180101); A61P 37/00 (20180101); A61P
19/02 (20180101); A61P 25/00 (20180101); C07D
471/10 (20130101); A61P 43/00 (20180101); A61P
3/00 (20180101); C07D 487/08 (20130101); A61P
1/00 (20180101); C07D 213/73 (20130101); A61P
25/06 (20180101); A61P 9/02 (20180101); A61P
25/28 (20180101); A61P 25/16 (20180101); C07D
401/12 (20130101) |
Current International
Class: |
C07D
471/00 (20060101); C07D 451/04 (20060101); C07D
417/12 (20060101); C07D 451/00 (20060101); C07D
405/00 (20060101); C07D 405/12 (20060101); C07D
401/00 (20060101); C07D 401/10 (20060101); C07D
401/12 (20060101); C07D 487/08 (20060101); C07D
487/00 (20060101); C07D 213/00 (20060101); C07D
417/00 (20060101); C07D 213/73 (20060101); C07D
471/10 (20060101); C07D 409/00 (20060101); C07D
498/00 (20060101); C07D 498/08 (20060101); C07D
409/12 (20060101); A61K 031/444 (); A61K 031/442 ();
A61K 031/46 (); C07D 401/12 (); C07D 498/08 () |
Field of
Search: |
;546/276.7,16,20,125,112
;514/339,278,230.5,304,299,183,216,249 ;544/105,349
;540/477,582 |
References Cited
[Referenced By]
U.S. Patent Documents
Other References
Parkash L et al. Curr. Sci. 58(17), 967-70, 1989.* .
Verma SS et al. J. Indian Chem. Soc. 65(11), 789-9, 1988..
|
Primary Examiner: Huang; Evelyn Mei
Attorney, Agent or Firm: Richardson; Peter C. Ginsburg; Paul
H. DeBenedictis; Karen
Parent Case Text
This application claims the benefit of provisional application No.
60/014,343, filed on Mar. 29, 1996.
Claims
What is claimed is:
1. A compound of the formula ##STR10##
and the pharmaceutically acceptable salts thereof, wherein
R.sup.1 and R.sup.2 form, together with the nitrogen to which they
are attached, an azabicyclic ring containing from 6 to 14 ring
members, from 1 to 3 of which are nitrogen and the rest of which
are carbon;
n is 0,1 or 2; and each carbon of said (CH.sub.2).sub.n can
optionally be substituted with a substituent R.sup.8 ;
m is 0,1, or 2; and each carbon of said (CH.sub.2).sub.m can
optionally be substituted with a substituent R.sup.9 ;
each R.sup.8 and each R.sup.9 is selected, independently, from
(C.sub.1 -C.sub.4)alkyl, aryl-(C.sub.1 -C.sub.4)alkyl wherein said
aryl is selected from phenyl and naphthyl; allyl and phenallyl;
X and Y are selected, independently, from methyl, methoxy, hydroxy
and hydrogen; and
R.sup.10 is hydrogen or (C.sub.1 -C.sub.6) alkyl;
with the proviso that R.sup.8 is absent when n is zero and R.sup.9
is absent when m is zero;
or a pharmaceutically acceptable salt of such compound.
2. A compound according to claim 1 wherein NR.sup.1 R.sup.2 is a
group of the formula ##STR11##
wherein NR.sup.3 R.sup.4 is NH.sub.2.
3. A compound according to claim 1 wherein NR.sup.1 R.sup.2 is a
group of the formula ##STR12##
wherein R.sup.5 is aralkyl and R.sup.6 is
(4-fluoro)phenylacetyl.
4. A pharmaceutical composition comprising a compound according to
claim 1, and a pharmaceutically acceptable carrier.
5. A method of inhibiting NOS in a mammal, comprising administering
to said mammal a NOS inhibiting effective amount of a compound
according to claim 1.
6. A method according to claim 4, wherein the mammal is suffering
from a condition selected from the group consisting of migraine,
inflammatory diseases, stroke, acute and chronic pain, hypovolemic
shock, traumatic shock, reperfusion injury, Crohn's disease,
ulcerative colitis, septic shock, multiple sclerosis, AIDS
associated dementia, neurodegenerative diseases, neuron toxicity,
Alzheimer's disease, chemical dependencies and addictions, emesis,
epilepsy, anxiety, psychosis, head trauma, adult respiratory
distress syndrome (ARDS), morphine induced tolerance and withdrawal
symptoms, inflammatory bowel disease, osteoarthritis, rheumatoid
arthritis, ovulation, dilated cardiomyopathy, acute spinal cord
injury, Huntington's disease, Parkinson's disease, glaucoma,
macular degeneration, diabetic neuropathy, diabetic nephropathy and
cancer in a mammal, comprising administering to said mammal a NOS
inhibiting effective amount of a compound according to claim 1.
7. A compound selected from the following:
6-((2-(6-(t-butoxycarbonylamino)-3-azabicyclo[3.1.
0]hex-3-yl)ethyl)phenyl)-pyridin-2-ylamine;
3-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-3-azabicyclo[3.1.
0]hex-6-ylamine;
6-{4-[2-(3,4-Dihydro-1H-isoquinolin-2-yl)-ethyl]-phenyl}-pyridin-2-ylamine;
6-{4-[2-(5-Methyl-2,5-diaza-bicyclo[2.2.
1]hept-2-yl)-ethyl]-phenyl}-pyridin-2-ylamine;
6-{4-[2-(8-Aza-spiro[4.5]dec-8-yl)-ethyl]-phenyl}-pyridin-2-ylamine;
6-{4-[2-(1,3-Dihydro-isoindol-2-yl)-ethyl]-phenyl}-pyridin-2-ylamine;
2-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-1,2,3,4-tetrahydro-isoquinoli
ne-3-carboxylic acid;
1-(3-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-3-aza-bicyclo[3.1.
0]hex-6-yl)-3-phenyl-urea;
(3-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-3-aza-bicyclo[3.1.
0]hex-6-yl)-dimethyl-amine;
N-(3-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-3-aza-bicyclo[3.1.
0]hex-6-yl)-2-(4-fluoro-phenyl)-acetamide;
8-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-3-benzyl-1,3,8-triaza-spiro[4
.5]decane-2,4-dione;
3-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-3-aza-bicyclo[3.2.
1]oct-8-ylamine;
(3-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-3-aza-bicyclo[3.1.
0]hex-6-yl)-phenethyl-amine;
(3-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-3-aza-bicyclo[3.1.
0]hex-6-yl)-(3-phenyl-propyl)-amine hydrochloride salt;
2-(3-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-3-aza-bicyclo[3.1.
0]hex-6-ylamino)-acetamide;
8-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-3-phenethyl-1,3,8-triaza-spir
o[4.5]decane-2,4-dione;
8-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-8-aza-bicyclo[3.2.
1]oct-3-ylamine;
{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-(8-benzyl-8-aza-bicyclo[3.2.
1]oct-3-yl)-amine;
{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-(8-aza-bicyclo[3.2.
1]oct-3-yl)-amine;
1-(3-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethylamino}-8-aza-bicyclo[3.2.
1]oct-8-yl)-2-(4-fluoro-phenyl)-ethanone;
{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-(8-methyl-8-aza-bicyclo[3.2.
1]oct-3-yl)-amine;
{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-(3-benzyl-3-aza-bicyclo[3.1.
0]hex-6-yl)-amine;
{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-[8-(4-fluoro-benzyl)-8-aza-bicy
clo[3.2.1]oct-3-yl]-amine;
{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-[8-(4-chloro-benzyl)-8-aza-bicy
clo[3.2.1]oct-3-yl]-amine;
N-(8-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-8-aza-bicyclo[3.2.
1]oct-3-yl)-benzamide;
{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-(3-benzyl-3-aza-bicyclo[3.3.
1]non-9-yl)-amine;
N-(8-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-8-aza-bicyclo[3.2.
1]oct-3-yl)-2-(4-fluoro-phenyl)-acetamide;
N-(3-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-3-aza-bicyclo[3.3.
1]non-9-yl)-benzamide (anti-isomer);
N-(3-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-3-aza-bicyclo[3.3.
1]non-9-yl)-benzamide (syn-isomer);
3-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-3-aza-bicyclo[3.3.
1]non-9-yl)-ylamine;
3-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-3-aza-bicyclo[3.1.
0]hexane-6-carboxylic acid ethyl ester;
3-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-3-aza-bicyclo[3.1.
0]hexane-6-carboxylic acid;
3-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-3-aza-bicyclo[3.1.
0]hex-6-ylamine (anti-isomer);
(3-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-3-aza-bicyclo[3.1.
0]hex-6-yl)-(4-methyl-piperazin-1-yl)-methanone;
{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-(9-benzyl-3-oxa-9-benzyl-3-oxa-
9-aza-bicyclo[3.3.1]non-7-yl)-amine (more polar diastereomer);
{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-(9-benzyl-3-oxa-9-aza-bicyclo[3
.3.1]non-7-yl)-amine (less polar diastereomer);
{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-(3-oxa-9-aza-bicyclo[3.3.
1]non-7-yl)-amine;
9-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-3-oxa-9-aza-bicyclo[3.3.
1]non-7-ylamine;
{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-(3-oxa-9-aza-bicyclo[3.3.
1]non-7-yl)-amine; and
6-{4-[2-(4-(Isoquinolin-1-yl)-piperazin-1-yl)-ethyl]-phenyl}-pyridin-2-ylam
ine;
or a pharmaceutically acceptable salt thereof.
8. A compound according to claim 1, wherein R.sup.1 and R.sup.2,
together with the nitrogen to which they are attached, form an
azabicyclic ring selected from the following: ##STR13##
wherein R.sup.3 and R.sup.4 are selected from hydrogen, (C.sub.1
-C.sub.6)alkyl, phenyl, naphthyl, (C.sub.1
-C.sub.6)alkyl-C(.dbd.O)--, HC(.dbd.O)--, (C.sub.1
-C.sub.6)alkoxy-(C.dbd.O)--, phenyl-C(.dbd.O)--,
naphthyl-C(.dbd.O)--, and (R.sup.7).sub.2 NC(.dbd.O)-- wherein each
R.sup.7 is selected, independently, from hydrogen and (C.sub.1
-C.sub.6)alkyl; and
R.sup.5 is selected from hydrogen, (C.sub.1 -C.sub.6)alkyl, phenyl,
naphthyl, phenyl-(C.sub.1 -C.sub.6)alkyl- and naphthyl(C.sub.1
-C.sub.6)alkyl-.
9. A compound according to claim 1, wherein such compound is
selected from:
3-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-3-aza-bicyclo[3.1.
0]hex-6-ylamine;
{2-[4-(6-Amino-pyridin-2-yl)-plenyl]-ethyl}-(3-oxa-9-aza-bicyclo[3.3.
1]non-7-yl)-amine;
(3-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-3-aza-bicyclo[3.1.
0]hex-6-yl)-dimethyl-amine;
8-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-3-benzyl-1,3,8-triaza-spiro[4
.5]decane-2,4-dione;
8-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-8-aza-bicyclo[3.2.
1]oct-3-ylamine;
3-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-3-aza-bicyclo[3.2.
1]oct-8-ylamine; and
6-{4-[2-(8-Aza-spiro[4.5]dec-8-yl)-ethyl]-phenyl}-pyridin-2-ylamine;
and the pharmaceutically acceptable salts of these compounds.
Description
The present invention relates to certain 6-phenylpyridyl-2-amine
derivatives that exhibit activity as nitric oxide synthase (NOS)
inhibitors, to pharmaceutical compositions containing them and to
their use in the treatment and prevention of central nervous system
disorders, inflammatory disorders, septic shock and other
disorders.
There are three known isoforms of NOS--an inducible form (I-NOS)
and two constitutive forms referred to as, respectively, neuronal
NOS (N-NOS) and endothelial NOS (E-NOS). Each of these enzymes
carries out the conversion of arginine to citrulline while
producing a molecule of nitric oxide (NO) in response to various
stimuli. It is believed that excess nitric oxide (NO) production by
NOS plays a role in the pathology of a number of disorders and
conditions in mammals. For example, NO produced by I-NOS is thought
to play a role in diseases that involve systemic hypotension such
as toxic shock and therapy with certain cytokines. It has been
shown that cancer patients treated with cytokines such as
interleukin 1 (IL-1), interleukin 2 (IL-2) or tumor necrosis factor
(TNF) suffer cytokine-induced shock and hypotension due to NO
produced from macrophages, i.e., inducible NOS (I-NOS), see
Chemical & Engineering News, December 20, p. 33, (1993). I-NOS
inhibitors can reverse this. It is also believed that I-NOS plays a
role in the pathology of diseases of the central nervous system
such as ischemia. For example, inhibition of I-NOS has been shown
to ameliorate cerebral ischemic damage in rats, see Am. J.
Physiol., 268, p. R286 (1995)). Suppression of adjuvant induced
arthritis by selective inhibition of I-NOS is reported in Eur. J.
Pharmacol., 273, p. 15-24 (1995).
NO produced by N-NOS is thought to play a role in diseases such as
cerebral ischemia, pain, and opiate tolerance. For example,
inhibition of N-NOS decreases infarct volume after proximal middle
cerebral artery occlusion in the rat, see J. Cerebr. Blood Flow
Metab., 14, p. 924-929 (1994). N-NOS inhibition has also been shown
to be effective in antinociception, as evidenced by activity in the
late phase of the formalin-induced hindpaw licking and acetic
acid-induced abdominal constriction assays, see Br. J. Pharmacol.,
110, p. 219-224 (1993). Finally, opioid withdrawal in rodents has
beer reported to be reduced by N-NOS inhibition, see
Neuropsychopharmacol., 13, p. 269-293 (1995).
SUMMARY OF THE INVENTION
This invention relates to compounds of the formula ##STR1##
and the pharmaceutically acceptable salts thereof, wherein
R.sup.1 and R.sup.2 are selected, independently, from (C.sub.1
-C.sub.6) alkyl, tetrahydronaphthalene and aralkyl, wherein the
aryl moiety of said aralkyl is phenyl or naphthyl and the alkyl
moiety i:s straight or branched and contains from 1 to 6 carbon
atoms, and wherein said (C.sub.1 -C.sub.6) alkyl and said
tetrahydronaphthalene and the aryl moiety of said aralkyl may
optionally be substituted with from one to three substituents,
preferably from zero to two substituents, that are selected,
independently, from halo (e.g., chloro, fluoro, bromo, iodo),
nitro, hydroxy, cyano, amino, (C.sub.1 -C.sub.4) alkoxy, and
(C.sub.1 -C.sub.4) alkylamino;
or R.sup.1 and R.sup.2 form, together with the nitrogen to which
they are attached, a piperazine, piperidine or pyrrolidine ring or
an azabicyclic ring containing from 6 to 14 ring members, from 1 to
3 of which are nitrogen and the rest of which are carbon, wherein
examples of said azabicyclic rings are the following ##STR2##
wherein R.sup.3 and R.sup.4 are selected from hydrogen, (C.sub.1
-C.sub.6)alkyl, phenyl, naphthyl, (C.sub.1
-C.sub.6)alkyl-C(.dbd.O)--, HC(.dbd.O)--, (C.sub.1
-C.sub.6)alkoxy-(C.dbd.O)--, phenyl-C(.dbd.O)--,
naphthyl-C(.dbd.O)--, and --(R.sup.7).sub.2 NC(.dbd.O)-- wherein
each R.sup.7 is selected, independently, from hydrogen and (C.sub.1
-C.sub.6)alkyl;
R.sup.5 is selected from hydrogen, (C.sub.1 -C.sub.6)alkyl, phenyl,
naphthyl, phenyl-(C.sub.1 -C.sub.6)alkyl- and naphthyl(C.sub.1
-C.sub.6)alkyl-;
and wherein said piperazine, piperidine and pyrrolidine rings may
optionally be substituted with one or more substituents, preferably
with from zero to two substituents that are selected,
independently, from (C.sub.1 -C.sub.6)alkyl, amino, (C.sub.1
-C.sub.6) alkylamino, [di-(C.sub.1 -C.sub.6)alkyl]amino, phenyl
substituted 5 to 6 membered heterocyclic rings containing from 1 to
4 rings nitrogen atoms, benzoyl, benzoylmethyl, benzylcarbonyl,
phenylaminocarbonyl, phenylethyl and phenoxycarbonyl, and wherein
the phenyl moieties of any of the foregoing substituents may
optionally be substituted with one or more substituents, preferably
with from zero to two substituents, that are selected,
independently, from halo, (C.sub.1 -C.sub.3)alkyl, (C.sub.1
-C.sub.3)alkoxy, nitro, amino, cyano, CF.sub.3 and OCF.sub.3 ;
n is 0,1 or 2; and each carbon of said (CH.sub.2).sub.n can
optionally be substituted with a substituent R.sup.8 ;
m is 0,1, or 2; and each carbon of said (CH.sub.2).sub.m can
optionally be substituted with a substituent R.sup.9 ;
each R.sup.8 and each R.sup.9 is selected, independently, from
(C.sub.1 -C.sub.4)alkyl, aryl-(C.sub.1 -C.sub.4)alkyl wherein said
aryl is selected from phenyl and naphthyl; allyl and phenallyl;
X and Y are selected, independently, from methyl, methoxy, hydroxy
and hydrogen; and
R.sup.10 is H(C.sub.1 -C.sub.6) alkyl;
with the proviso that R.sup.8 is absent when n is zero and R.sup.9
is absent when m is zero.
The present invention also relates to the pharmaceutically
acceptable acid addition salts of compounds of the formula I. The
acids which are used to prepare the pharmaceutically acceptable
acid addition salts of the aforementioned base compounds of this
invention are those which form non-toxic acid addition salts, i.e.,
salts containing pharmacologically acceptable anions, such as the
hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate,
bisulfate, phosphate, acid phosphate, acetate, lactate, citrate,
acid citrate, tartrate, bitartrate, succinate, maleate, fumarate,
gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate,
benzenesulfonate, p-toluenesulfonate and pamoate [i.e.,
1,1-methylene-bis-(2-hydroxy-3-naphthoate)] salts.
The term "alkyl", as used herein, unless otherwise indicated,
includes saturated monovalent hydrocarbon radicals having straight,
branched or cyclic moieties or combinations thereof.
The term "one or more substituents", as used herein, refers to a
number of substituents that equals from one to the maximum number
of substituents possible based on the number of available bonding
sites.
The term "halo", as used herein, unless otherwise indicated,
includes chloro, fluoro, bromo and iodo.
Examples of preferred compounds of this invention are compounds of
the formula I, and their pharmaceutically acceptable salts, wherein
NR.sup.1 R.sup.2 is:
4-phenoxycarbonylpiperazin-1-yl;
4-(4-fluorophenylacetyl)piperazin-1-yl;
4-phenylethylpiperazin-1-yl;
4-phenoxymethylcarbonylpiperazin-1-yl;
4-phenylaminocarbonylpiperazin-1-yl;
4-benzoylmethylpiperazin-1-yl; or
4-benzylcarbonylpiperazin-1-yl.
Other preferred compounds of this invention are compounds of the
formula I, and their pharmaceutically acceptable salts, wherein
NR.sup.1 R.sup.2 is a group of the formula ##STR3##
wherein NR.sup.3 R.sup.4 is NH.sub.2.
Other preferred compounds of this invention are compounds of the
formula I, and their pharmaceutically acceptable salts, wherein
NR.sup.1 R.sup.2 is a group of the formula ##STR4##
wherein R.sup.5 is aralkyl, e.g., benzyl, and R.sup.6 is
(4-fluoro)phenylacetyl.
Specific preferred compounds of the present invention include the
following:
1-4-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-piperazin-1-yl)-ethanone;
1-(4-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-piperazin-1-yl)-2-methoxy-
ethanone;
1-(4-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-piperazin-1-yl)-2-phenoxy-
ethanone;
(4-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-piperazin-1-yl)-cyclopentyl-
methanone;
1-(4-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-piperazin-1-yl)-2-phenyl-e
thanone;
3-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-3-aza-bicyclo[3.1.
0]hex-6-ylamine;
2-(4-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-piperazin-1-yl)-1-phenyl-e
thanone;
1-(4-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-piperazin-1-yl)-2-(4-fluor
o-phenyl)-ethanone;
6-{4-[2-(4-Phenethyl-pipereizin-1-yl)-ethyl]-phenyl}-pyridin-2-ylamine;
2-(4-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-piperazin-1-yl)-1-phenyl-e
thanol;
{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-(3-oxa-9-aza-bicyclo[3.3.
1]non-7-yl)-amine;
6-(4-{2-[4-(2-Amino-2-phenyl-ethyl)-piperazin-1-yl]-ethyl}-phenyl)-pyridin-
2-ylamine;
6-{4-[2-(4-Amino-2,6-dimethyl-piperidin-1-yl)-ethyl]-phenyl}-pyridin-2-ylam
ine;
6-{4-[2-(4-Methyl-piperazin-1-yl)-ethyl]-phenyl}-pyridin-2-ylamine;
(3-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-3-aza-bicyclo[3.1.
0]hex-6-yl)-dimethyl-amine;
6-[4-(2-Amino-ethyl)-phenyl]-pyridin-2-ylamine;
6-{4-[2-(8-Aza-spiro[4.5]dec-8-yl)-ethyl]-phenyl}-pyridin-2-ylamine;
6-{4-[2-(4-Isobutyl-piperazin-1-yl)-ethyl]-phenyl}-pyridin-2-ylamine;
2-(4-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-piperazin-1-yl)-N-isopropy
l-acetamide;
4-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-piperazine-1-carboxylic
acid p-tolyl-amide;
6-(4-{2-[4-(3-Phenyl-propyl)-piperazin-1-yl]-ethyl}-phenyl)-pyridin-2-ylami
ne;
1-(4-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-piperazin-1-yl)-2-(4-chlor
o-phenyl)-ethanone;
8-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-3-benzyl-1,3,8-triaza-spiro[4
.5]decane-2,4-dione;
N-(1-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-pyrrolidin-3-yl)-2-(4-fluo
ro-phenyl)-acetamide;
8-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-8-aza-bicyclo[3.2.
1]oct-3-ylamine;
3-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-3-aza-bicyclo[3.2.
1]oct-8-ylamine;
2-Amino-1-(4-{2-[4-(6-amino-pyridin-2-yl)-phenyl]-ethyl}-piperazin-1-yl)-3-
phenyl-propan-1-one;
6-{4-[2-(4-Amino-piperidin-1-yl)-ethyl]-phenyl}-pyridin-2-ylamine;
6-{4-[2-(4-Benzhydryl-piperiazin-1-yl)-ethyl]-phenyl}-pyridin-2-ylamine;
6-{4-[2-(4-Benzhydryl-piperidin-1-yl)-ethyl]-phenyl}-pyridin-2-ylamine;
6-{4-[(Cyclohexyl-methyl-amino)-methyl]-phenyl}-pyridin-2-ylamine;
6-{4-[(Cyclohexyl-methyl-amino)-methyl]-2-methoxy-phenyl}-pyridin-2-ylamine
;
6-[4-(Phenethylamino-methyl)-phenyl]-pyridin-2-ylamine;
6-[2-Methoxy-4-(phenethylamino-methyl)-phenyl]-pyridin-2-ylamine;
6-[4-(4-Amino-piperidin-1-ylmethyl)-phenyl}-pyridin-2-ylamine;
6-{4-[(Cyclohexyl-methyl-amino)-methyl]-2-fluoro-phenyl}-pyridin-2-ylamine;
Other compounds of the formula I include:
1-(4-{2-[4-(6-Amino-pyridin-2-yl)-2-methoxy-phenyl]-ethyl}-piperazin-1-yl)-
2-phenyl-ethanone;
6-{4-[2-(4-Isobutyl-piperazin-1-yl)-ethyl]-2-methoxy-phenyl}-pyridin-2-ylam
ine;
3-{2-[4-(6-Amino-pyridin-2-yl)-2-methoxy-phenyl]-ethyl}-3-aza-bicyclo[3.1.
0]hex-6-ylamine;
{2-[4-(6-Amino-pyridin-2-yl)-2-methoxy-phenyl]-ethyl}-(3-oxa-9-aza-bicyclo[
3.3.1]non-7-yl)-amine;
6-(4-{2-[4-(2-Amino-2-phenyl-ethyl)-piperazin-1-yl]-ethyl}-2-methoxy-phenyl
)-pyridin-2-ylamine;
6-{4-[2-(4-Amino-2-methoxy-piperidin-1-yl)-ethyl]-2-methoxy-phenyl}-pyridin
-2-ylamine;
2-(4-{2-[4-(6-Amino-pyridin-2-yl)-2-methoxy-phenyl]-ethyl}-piperazin-1-yl)-
N-isopropyl-acetamide;
6-[4-(4-Amino-piperidin-1-ylmethyl)-2-methoxy-phenyl}-pyridin-2-ylamine;
1-(4-{2-[4-(6-Amino-pyridin-2-yl)-2-methyl-phenyl]-ethyl}-piperazin-1-yl)-2
-phenyl-ethanone;
6-{4-[2-(4-Isobutyl-piperazin-1-yl)-ethyl]-2-methyl-phenyl}-pyridin-2-ylami
ne;
3-{2-[4-(6-Amino-pyridin-2-yl)-2-methyl-phenyl]-ethyl}-3-aza-bicyclo[3.1.
0]hex-6-ylamine;
2-(4-{2-[4-(6-Amino-pyridin-2-yl)-2-methyl-phenyl]-ethyl}-piperazin-1-yl)-p
henyl-ethanone;
1-(4-{2-[4-(6-Amino-pyridin-2-yl)-2-methyl-phenyl]-ethyl}-piperazin-1-yl)-2
-(4-fluoro-phenyl)-ethanone;
6-{4-[2-(4-Phenethyl-pipereizin-1-yl)-ethyl]-2-methyl-phenyl}-pyridin-2-yla
mine;
2-(4-{2-[4-(6-Amino-pyridin-2-yl)-2-methyl-phenyl]-ethyl}-piperazin-1-yl)-1
-phenyl-ethanol;
{2-[4-(6-Amino-pyridin-2-yl)-2-methyl-phenyl]-ethyl}-(3-oxa-9-aza-bicyclo[3
.3.1]non-7-yl)-amine;
6-(4-{2-[4-(2-Amino-2-phenyl-ethyl)-piperazin-1-yl]-ethyl}-2-methyl-phenyl)
-pyridin-2-ylamine;
6-{4-[2-(4-Amino-2,6-dimethyl-piperidin-1-yl)-ethyl]-2-methyl-phenyl}-pyrid
in-2-ylamine;
2-(4-{2-[4-(6-Amino-pyridin-2-yl)-2-methyl-phenyl]-ethyl}-piperazin-1-yl)-N
-isopropyl-acetamide;
6-[4-(4-Amino-piperidin-1-ylmethyl)-2-methyl-phenyl}-pyridin-2-ylamine;
N-(1-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-pyrrolidin-3-yl)-2-phenyl-
acetamide;
N-(1-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-pyrrolidin-3-yl)-2-(3-trif
luoromethylphenyl)-acetamide;
N-(1-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-pyrrolidin-3-yl)-2-(4-toly
l)-acetamide;
N-(1-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-pyrrolidin-3-yl)-2-(4-meth
oxyphenyl)-acetamide;
2-(4-{2-[4-(6-Amino-pyridin-2-yl)-2-methoxy-phenyl]-ethyl}-piperazin-1-yl)-
1-phenyl-ethanone;
1-(4-{2-[4-(6-Amino-pyridin-2-yl)-2-methoxy-phenyl]-ethyl}-piperazin-1-yl)-
2-(4-fluoro-phenyl)-ethanone;
N-(1-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-pyrrolidin-3-yl)-2-cyclohe
xyl-acetamide;
2-(4-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-piperazin-1-yl)-1-(4-tolyl
)-ethanone;
2-(4-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-piperazin-1-yl)-1-(4-metho
xyphenyl)-ethanone;
2-(4-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-piperazin-1-yl)-1-(4-chlor
ophenyl)-ethanone;
2-(4-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-piperazin-1-yl)-1-(4-fluor
ophenyl)-ethanone;
2-(4-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-piperazin-1-yl)-1-cyclohex
yl-ethanone;
1-(4-{2-[4-(6-Amino-pyridin-2-yl)-2-fluoro-phenyl]-ethyl}-piperazin-1-yl)-2
-phenyl-ethanone;
6-{4-[2-(4-Isobutyl-piperazin-1-yl)-ethyl]-2-fluoro-phenyl}-pyridin-2-ylami
ne;
3-{2-[4-(6-Amino-pyridin-2-yl)-2-fluoro-phenyl]-ethyl}-3-aza-bicyclo[3.1.
0]hex-6-ylamine;
2-(4-{2-[4-(6-Amino-pyridin-2-yl)-2-fluoro-phenyl]-ethyl}-piperazin-1-yl)-1
-phenyl-ethanone;
1-(4-{2-[4-(6-Amino-pyridin-2-yl)-2-fluoro-phenyl]-ethyl}-piperazin-1-yl)-2
-(4-fluoro-phenyl)-ethanone;
6-{4-[2-(4-Phenethyl-piperazin-1-yl)-ethyl]-2-fluoro-phenyl}-pyridin-2-ylam
ine;
2-(4-{2-[4-(6-Amino-pyridin-2-yl)-2-fluoro-phenyl]-ethyl}-piperazin-1-yl)-1
-phenyl-ethanol;
{2-[4-(6-Amino-pyridin-2-yl)-2-fluoro-phenyl]-ethyl}-(3-oxa-9-aza-bicyclo[3
.3.1]non-7-yl)-amine;
6-(4-{2-[4-(2-Amino-2-phenyl-ethyl)-piperazin-1-yl]-ethyl}-2-fluoro-phenyl)
-pyridin-2-ylamine;
6-{4-[2-(4-Amino-2-fluoro-piperidin-1-yl)-ethyl]-2-fluoro-phenyl}-pyridin-2
-ylamine;
2-(4-{2-[4-(6-Amino-pyridin-2-yl)-2-fuoro-phenyl]-ethyl}-piperazin-1-yl)-N-
isopropyl-acetamide;
6-[4-(4-Amino-piperidin-1-ylmethyl)-2-fluoro-phenyl}-pyridin-2-ylamine;
6-{4-[2-(4-Amino-2,6-diethyl-piperidin-1-yl)-ethyl]-phenyl}-pyridin-2-ylami
ne;
6-{4-[2-(4-Amino-2,6-dibenzyl-piperidin-1-yl)-ethyl]-phenyl}-pyridin-2-ylam
ine;
{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-(9-(4-fluoro)-benzyl-3-oxa-9-az
a-bicyclo[3.3.1]non-7-yl)-amine;
{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-(9-(4-chloro)-benzyl-3-oxa-9-az
a-bicyclo[3.3.1]non-7-yl)-amine;
{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-(9-(4-methyl)-benzyl-3-oxa-9-az
a-bicyclo[3.3.1]non-7-yl)-amine; and
{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-(9-(4-methoxy)-benzyl-3-oxa-9-a
za-bicyclo[3.3.1]non-7-yl)-amine.
The present invention also relates to a pharmaceutical composition
for treating or preventing a condition selected from the group
consisting of migraine inflammatory diseases (e.g., asthma),
stroke, acute and chronic pain, hypovolemic shock, traumatic shock,
reperfusion injury, Crohn's disease, ulcerative colitis, septic
shock, multiple sclerosis, AIDS associated dementia,
neurodegenerative diseases, neuron toxicity, Alzheimer's diseaise,
chemical dependencies and addiction (e.g., dependencies on drugs,
alcohol and nicotine), emesis, epilepsy, anxiety, psychosis, head
trauma, adult respiratory distress syndrome (ARDS), morphine
induced tolerance and withdrawal symptoms, inflammatory bowel
disease, osteoarthritis, rheumatoid arthritis, ovulation, dilated
cardiomyopathy, acute spinal cord injury, Huntington's disease,
Parkinson's disease, glaucoma, macular degeneration, diabetic
neuropathy, diabetic nephropathy and cancer in a mammal, including
a human, comprising an amount of a compound of the formula I, or a
pharmaceutically acceptable salt thereof that is effective in
treating or preventing such condition, and a pharmaceutically
acceptable carrier.
The present invention also relates to a method of treating or
preventing a condition selected from the group consisting of
migraine inflammatory diseases (e.g., asthma), stroke, acute and
chronic pain, hypovolemic shock, traumatic shock, reperfusion
injury, Crohn's disease, ulcerative colitis, septic shock, multiple
sclerosis, AIDS associated dementia, neurode-generative diseases,
neuron toxicity, Alzheimer's disease, chemical dependencies and
addictions (e.g., dependencies on drugs, alcohol and nicotine),
emesis, epilepsy, anxiety, psychosis, head trauma, adult
respiratory distress syndrome (ARDS), morphine induced tolerance
and withdrawal symptoms, inflammatory bowel disease,
osteoarthritis, rheumatoid arthritis, ovulation, dilated
cardiomyopathy, acute spinal cord injury, Huntington's disease,
Parkinson's disease, glaucoma, macular degeneration, diabetic
neuropathy, diabetic nephropathy and cancer in a mammal, including
a human, comprising administering to said mammal an amount of a
compound of the formula I, or a pharmaceutically acceptable salt
thereof, that is effective in treating or preventing such
condition.
The present invention also relates to a pharmaceutical composition
for inhibiting nitric oxide synthase (NOS) in a mammal, including a
human, comprising an NOS inhibiting effective amount of a compound
of the formula I, or a pharmaceutically acceptable salt thereof and
a pharmaceutically acceptable carrier.
The present invention also relates to a method of inhibiting NOS in
a mammal, including a human, comprising administering to said
mammal a NOS inhibiting effective amount of a compound of the
formula I, or a pharmaceutically acceptable salt thereof.
The present invention also relates to a pharmaceutical composition
for treating or preventing a condition selected from the group
consisting of migraine, inflammatory diseases (e.g., asthma),
stroke, acute and chronic pain, hypovolemic shock, traumatic shock,
reperfusiori injury, Crohn's disease, ulcerative colitis, septic
shock, multiple sclerosis, AIDS associated dementia,
neurodegenerative diseases, neuron toxicity, Alzheimer's disease,
chemical dependencies and addictions (e.g., dependencies on drugs,
alcohol and nicotine), emesis, epilepsy, anxiety, psychosis, head
trauma, adult respiratory distress syndrome (ARDS), morphine
induced tolerance and withdrawal symptoms, inflammatory bowel
disease, osteoarthritis, rheumatoid arthritis ovulation, dilated
cardiomyopathy, acute spinal cord injury, Huntington's disease,
Parkinson's disease, glaucoma, macular degeneration, diabetic
neuropathy, diabetic nephropathy and cancer in a mammal, including
a human, comprising a NOS inhibiting effective amount of a compound
of the formula I, or a pharmaceutically acceptable salt thereof and
a pharmaceutically acceptable carrier.
The present invention also relates to a method of treating or
preventing a condition selected from the group consisting of
migraine, inflammatory diseases (e.g., asthma), stroke, acute and
chronic pain, hypovolemic shock, traumatic shock, reperfusion
injury, Crohn's disease, ulcerative colitis, septic shock, multiple
sclerosis, AIDS associated dementia, neurodegenerative diseases,
neuron toxicity, Alzheimer's disease, chemical dependencies and
addictions (e.g., dependencies on drugs, alcohol or nicotine),
emesis, epilepsy, anxiety, psychosis, head trauma, adult
respiratory distress syndrome (ARDS), morphine induced tolerance
and withdrawal symptoms, inflammatory bowel disease,
osteoarthritis, rheumatoid arthritis, ovulation, dilated
cardiomyopathy, acute spinal cord injury, Huntington's disease,
Parkinson's disease, glaucoma, macular degeneration, diabetic
neuropathy, diabetic nephropathy and cancer in a mammal, including
a human, comprising administering to said mammal a NOS inhibiting
effective amount of a compound of the formula II, or a
pharmaceutically acceptable salt thereof.
Compounds of formula I have chiral centers and therefore may exist
in different enantiomeric and diasterilomic forms. This invention
relates to all optical isomers and all stereoisomers of compounds
of the formula I and mixtures thereof, and to all pharmaceutical
compositions and methods of treatment defined above that contain or
employ them, respectively.
Formulae I and II above include compounds identical to those
depicted but for the fact that one or more hydrogen, carbon or
other atoms are replaced by isotopes thereof. Such compounds may be
useful as research and diagnostic tools in metabolism
pharmacokinetic studies and in binding assays.
DETAILED DESCRIPTION OF THE INVENTION
The compounds of the formula I may be prepared as described in the
following reaction schemes and discussion. Unless otherwise
indicated, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6,
R.sup.7, R.sup.8, R.sup.9 and R.sup.10 and structural formula I in
the reaction schemes and discussion that follow are defined as
above. ##STR5## ##STR6## ##STR7## ##STR8## ##STR9##
The starting materials used in the procedure of Scheme 1 are either
commercially available, known in the art or readily obtainable form
known compounds by methods that will be apparent to those skilled
in the art. Referring to Scheme 1, the conversion of the compound
of formula II into the compound of formula III may be carried out
by first converting the compound of formula II into the
corresponding 2-amino compound by reacting it with ammonia in a
polar hydroxylic or polar nonhydroxylic solvent at a temperature of
about 100.degree. C. to about 250.degree. C. and a pressure of
about 50 to about 500 p.s.i. for about 1 to 24 hours, preferably
using a stainless steel bomb. The pyrrolyl group is then added
using hexane-2,5-dione, either neat or in a non-polar solvent such
as toluene, in the presence of an acidic catalyst such as acetic
acid or hydrochloric acid, at a temperature from about room
temperature to about the reflux temperature, generally the latter,
for about 1 to 72 hours.
The conversion of the compound of formula III formed in the above
reaction into the compound of formula IV is carried out using a
transition metal mediated coupling reaction with a suitably
substituted aryl iodide or bromide. More specifically, the lithium
derivative of the compound of formula III is generated in an
ethereal or hydrocarbon solvent at a temperature from about
-100.degree. C. to about room temperature, preferably at about
-78.degree. C., using an alkyl lithium such as butyl lithium, for
about 10 to 120 minutes, followed by addition of a catalytic metal
reagent such as zinc chloride and warming to room temperature to
effect transmetalation. This is followed by addition of the aryl
iodide (e.g., 1-iodo-4-(2-chloroethyl)benzene) or bromide and a
transition mietal, such as palladium in the form of
tetrakistriphenylphosphine palladium, followed by heating to a
temperature of about 30.degree. C. to about 100.degree. C.,
typically to about the reflux temperature of the solvent, for about
1 to 24 hours.
The conversion of the compound of formula IV to the desired
compound of formula I is accomplished by first removing the
pyrrolyl protecting group using, typically, hydroxylamine or
hydroxylamine hydrochloride in a polar, protic solvent such as an
alcohol, at a temperature of from about room temperature to about
150.degree. C., generally at about the reflux temperature of the
solvent, for about 1 to 72 hours. This is followed by addition of
the appropriate NR.sup.1 R.sup.2 group by displacement of the
chloro group with an amine of the formula HNR.sup.1 R.sup.2 using a
polar, aprotic or a polar, protic solvent such as an alcohol,
dimethylformamide (DMF), methylisobutylketone or
N-methylpyrrolidone (NMP), optionally in the presence of a catalyst
such as sodium iodide, at ia temperature of from about room
temperature to about 200.degree. C., typically at about the reflux
temperature of the solvent, or at about 140.degree. C. in the cases
of dimethylformamide and N-methylpyrrolidone, for about 100 hours,
generally from about 12 to 24 hours.
Referring to Scheme 2, ciompound VI is prepared by reacting V with
p-formylbenzeneboronic acid in a solvent consisting of an alcohol,
preferably ethanol, optionally mixed with water of a halogenated
hydrocarbon, at a temperature from 25.degree. C. to 150.degree. C.,
for a time from 1 to 24 hours, using a palladium-based catalyst,
either palladium-zero or palladium-two oxidation state, typically
with phosphine ligands, preferably tetrakis-triphenylphosphine
palladium. Compound VII is prepared by reacting VI with
tosylmethylisocyanide in the presence of potassium t-butoxide and
ethanol, in an ethereal solvent such as 1,2-dimethoxyethane, at a
temperature from -100.degree. C. to 100.degree. C., for a time from
1 to 24 hours. Compound VIII is prepared from VII by basic
hydrolysis of the nitrile using an alkali metal hydroxide in an
aqueous alcohol-based solvent, such as aqueous ethanol, at a
temperature from 25.degree. C. to 125.degree. C., for a time from
30 minutes to 48 hours. Compound IX is prepared from VIII by
dehydrative coupling with ammonia, a primary amine, or a secondary
amine effected by a dehydrating agent such as a carbodiimide, for
example, N-ethyl-N-(dimethylaminopropyl)-carbodiimide, in a solvent
from a halogenated hydrocarbon or N,N-dialkylamide, such as
dirriethylformamide, at a temperature from 0.degree. C. to
100.degree. C., for a time from 1 to 48 hours. Compound X is
prepared from IX by deblocking using hydroxylamine hydrochloride in
an aqueous or alcoholic solvent, preferably aqueous ethanol, at a
temperature from 25.degree. C. to 100.degree. C., for a time from 1
to 48 hours, and may include deblocking a protecting group such a
the t-butoxycarbonyl group, by reaction with trifluoroacetic acid,
or a related polyhalogenated acetic acid, or a gaseous hydrogen
halide, such as HCl, in a halogenated hydrocarbon, ethereal solvent
or ethyl acetate, at a temperature from -70.degree. C. to
100.degree. C., for a time from 10 minutes to 24 hours. The final
compound in Scheme 2, I, is prepared by reduction of X with borane,
a trialkyl borane, alane, or lithium aluminum hydride in an
ethereal solvent, such as ethyl ether or tetrahydrofuran, at a
temperature from -100.degree. C. to 100.degree. C., for a time from
30 minutes to 24 hours, and optionally using cesium fluoride and an
alkali metal or alkaline earth carbonate in an aqueous alcoholic
solvent, at a temperature from 25.degree. C. to 125.degree. C. for
a time from 1 to 72 hours.
Referring to Scheme 3, compound XI is prepared by dehydrative
coupling of N-phenethylpiperazine with 4-bromophenylacetic acid
using a carbodiimide-based dehydrating reagent, such as N-ethyl,
N-(dimethylaminopropyl)-carbodiimide, in a solvent such as a
halogenated hydrocarbon or dialkylamide-based solvent, such as
dimethylformamide, at a temperature from 0.degree. C. to
100.degree. C. in a time from 1 to 48 hours. Compound XI was
converted to compound XII by reduction with borane, a trialkyl
borane, alane, or lithium aluminum hydride in an ethereal solvent,
such as ethyl ether or tetrahydrofuran, at i temperature from
-100.degree. C. to 100.degree. C., for a time from 30 minutes to 24
hours, and optionally using cesium fluoride and an alkali metal or
alkaline earth carbonate in an aqueous alcoholic solvent, at a
temperature from 25.degree. C. to 125.degree. C. for a time from 1
to 72 hours. Compound XII is then converted to the organolithium
derivative in the presence of an organolithium reagent, such as
butyl lithium, and added to
4-methyl-2-(2,5-dimethylpyrrolyl)-pyridine in an ethereal solvent,
such as ethyl ether, at a temperature from -70.degree. C. to
70.degree. C. in a time from 30 minutes to 24 hours. The final
compound in Scheme 3, compound I, is prepared by deblocking using
hydroxylamine hydrochloride in an aqueous or alcoholic solvent,
preferably aqueous ethanol, at a temperature from 25.degree. C. to
100.degree. C., for a time from 1 to 48 hours.
Referring to Scheme 4, compound XIV is prepared by dehydrative
coupling of dibenzylamine with 4-bromophenylacetic acid effected by
a dehydrating agent such as a carbodiimide, for example,
N-ethyl-N-(dimethylaminopropyl)-carbodiimide, in a solvent from a
halogenated hydrocarbon or N,N-dialkylamide, such as
dimethylformamide, at a temperature from 0.degree. C. to
100.degree. C., for a time from 1 to 48 hours. Compound XIV is
converted to compound XV by reduction with borane, a trialkyl
borane, alane, or lithium aluminum hydride in an ethereal solvent,
such as ethyl ether or tetrahydrofuran, at a temperature from
-100.degree. C. to 100.degree. C., for a time from 30 minutes to 24
hours, and optionally using cesium fluoride and an alkali metal or
alkaline earth carbonate in an aqueous alcoholic solvent, at a
temperature from 25.degree. C. to 125.degree. C. for a time from 1
to 72 hours. Compound XV is then converted to the organolithium
derivative in the presence of an organolithium reagent, such as
butyl lithium, and added to 2-(2,5-dimethylpyrrolyl)-pyridine in an
ethereal solvent, such as ethyl ether, at a temperature from
-70.degree. C. to 70.degree. C. in a time from 30 minutes to 24
hours to provide compound XVI. Compound XVII is then prepared from
compound XVI by hydrogenolysis with hydrogen or ammonium formate in
the presence of a noble metal catalyst, such as palladium, in an
ethereal, halogenated hydrocarbon, alcoholic, or aqueou.s alcoholic
solvent, at a temperature from 0.degree. C. to 100.degree. C. for a
time from 30 minutes to 24 hours. Compound XVIII is then prepared
from compound XVII by reductive amination with an aldehyde or
ketone in the presence of a borohydride-based reagent such as
sodium cyanoborohydride or sodium triacetoxyborohydride, in an
ethereal, halogenated hydrocarbon, alcoholic, or aqueous-alcoholic
solvent, at a temperature from 0.degree. C. to 100.degree. C. for a
time from 1 to 72 hours. Conversion of compound XVIII to I by
deblocking is carried out by using hydroxylamine hydrochloride in
an aqueous or alcoholic solvent, preferably aqueous ethanol, at a
temperature from 25.degree. C. to 100.degree. C., for a time from 1
to 48 hours.
Referring to Scheme 5, compound XIX is prepared by reaction of the
known (EP 470794 A1, see Chem. Abs., 116:193935)
2-bromo-5-methylanisole with an alkyl lithium, typically butyl
lithium, in an ethereal or hydrocarbon solvent, at a temperature
from -100.degree. C. to 0.degree. C. for 1 minute to 24 h, followed
by addition of an alkyl or aryl borate ester, typically triethyl
borate, at a temperature from -100.degree. C. to 0.degree. C., and
stirred while the temperature was adjusted to 0.degree. C. to the
reflux temperature of the solvent, typically 65.degree. C., for 1
to 48 hours. Compound XIX is converted to XX by reaction with
6-bromo-2-(2,5-dimethylpyrrolyl)pyridine and an alkali carbonate in
a solvent consisting of an alcohol, preferably ethanol, optionally
mixed with water of a halogenated hydrocarbon, at a temperature
from 25.degree. C. to 150.degree. C., for a time from 1 to 24
hours, using a palladium-based catalyst, either palladium-zero or
palladium-two oxidation state, typically with phosphine ligands,
preferably tetrakis-triphenylphosphine palladium. Compound XXI was
prepared from XX by first deblocking using hydroKylamine
hydrochloride in an aqueous or alcoholic solvent, preferably
aqueous ethanol, at a temperature from 25.degree. C. to 100.degree.
C., for a time from 1 to 48 hours, followed by reaction with
N-carbethoxyphthalimide in a hydrocarbon solvent at a temperature
from room temperature to the reflux temperature of the solvent or
180.degree. C., typically 110.degree. C., for a time from 1 to 48
hours. Conversion of compound XXI to XXII was carried out by
reaction with N-bromo succinimide in a chlorinated hydrocarbon
solvent, typically carbon tetrachloride, with a catalytic: amount
of a radical initiator such as azobisisobutyronitrile, at a
temperature from room temperature to 100.degree. C. for a time from
10 minutes to 24 hours. Compound XXII was then converted to XXIII
by reaction with an amine, such as phenethylamine, in a
hydrocarbon, halogenated hydrocarbon, ethereal, or polar aprotic
solvent, such as acetonitrile, with an alkali carbonate base, at a
temperature from room temperature to 100.degree. C. for a time from
10 minutes to 48 hours. Compound XXIII was then converted to the
final product in Scheme 5, I, by deblocking using hydrazine in an
alcoholic, aqueous, or ethereal solvent, at a temperature from room
temperature to 150.degree. C. for a time from 1 to 72 hours.
The preparation of other compounds of the formula I not
specifically described in the foregoing experimental section can be
accomplished using combinations of the reactions described above
that will be apparent to those skilled in the art.
In each of the reactions discussed or illustrated above, pressure
is not critical unless otherwise indicated. Pressures from about
0.5 atmospheres to about 5 atmospheres are generally acceptable,
and ambient pressure, i.e., about 1 atmosphere, is preferred as a
matter of convenience.
The compounds of formulae I ("the active compounds of this
invention") which are basic in nature are capable of forming a wide
variety of different salts with various inorganic and organic
acids. Although such salts must be pharmaceutically acceptable for
administration to animals, it is often desirable in practice to
initially isolate a compound of the formula I from the reaction
mixture as a pharmaceutically unacceptable salt and then simply
convert the latter back to the free base compound by treatment with
an alkaline reagent and subsequently convert the latter free base
to a pharmaceutically acceptable acid addition salt. The acid
addition salts of the active base compounds of this invention are
readily prepared by treating the base compound with a substantially
equivalent amount of the chosen mineral or organic acid in an
aqueous solvent medium or in a suitable organic solvent, such as
methanol or ethanol. Upon careful evaporation of the solvent, the
desired solid salt is readily obtained.
The active compounds of this invention and their pharmaceutically
acceptable salts are useful as NOS inhibitors i.e., they possess
the ability to inhibit the NOS enzyme in mammals, and therefore
they are able to function as therapeutic agents in the treatment of
the aforementioned disorders and diseases in an afflicted
mammal.
The active compounds of this invention and their pharmaceutically
acceptable salts can be administered via either the oral,
parenteral or topical routes. In general, these compounds are most
desirably administered in dosages ranging from about 0.01 to about
250 mg per day, in single or divided doses (i.e., from 1 to 4 doses
per day), although variations will necessarily occur depending upon
the species, weight and condition of the subject being treated and
the particular route of administration chosen. However, a dosage
level that is in the range of about 0.07 mg to about 21 mg per kg
of body weight per day is most desirably employed. Variations may
nevertheless occur depending upon the species of animal being
treated and its individual response to said medicament, as well as
on the type of pharmaceutical formulation chosen and the time
period and interval at which such administration is carried out. In
some instances, dosage levels below the lower limit of the
aforesaid range may be more than adequate, while in other cases
still larger doses may be employed without causing any harmful side
effect, provided that such larger doses are first divided into
several small doses for administration throughout the day.
The active compounds of the invention may be administered alone or
in combination with pharmaceutically acceptable carriers or
diluents by either of the three routes previously indicated, and
such administration may be carried out in single or multiple doses.
More particularly, the novel therapeutic agents of this invention
can be administered in a wide variety of different dosage forms,
i.e., they may be combined with various pharmaceutically acceptable
inert carriers in the form of tablets, capsules, lozenges, troches,
hard candies, powders, sprays, creams, salves, suppositories,
jellies, gels, pastes, lotions, ointments, aqueous suspensions,
injectable solutions, elixirs, syrups, and the like. Such carriers
include solid diluents or fillers, sterile aqueous medial and
various non-toxic organic solvents, etc. Moreover, oral
pharmaceutical compositions can be suitably sweetened and/or
flavored. In general, the therapeutically-effective compounds of
this invention are present in such dosage forms at concentration
levels ranging from about 5.0% to about 70% by weight.
For oral administration, tablets containing various excipients such
as microcrystalline cellulose, sodium citrate, calcium carbonate,
dicalcium phosphate and glycine may be employed along with various
disintegrants such as starch (and preferably corn, potato or
tapioca starch), alginic acid and certain complex silicates,
together with granulation binders like polyvinylpyrrolidone,
sucrose, gelatin and acacia. Additionally, lubricating agents such
as magnesium stearate, sodium lauryl sulfate and talc are often
very useful for tabletting purposes. Solid compositions of a
similar type may also be employed as fillers in gelatin capsules;
preferred materials in this connection also include lactose or milk
sugar as well as high molecular weight polyethylene glycols. When
aqueous suspensions and/or elixirs are desired for oral
administration, the active ingredient may be combined with various
sweetening or flavoring agents, coloring matter or dyes, and, if so
desired, emulsifying and/or suspending agents as well, together
with such diluents as water, ethanol, propylene glycol, glycerin
and various like combinations thereof.
For parenteral administration, solutions of an active compound of
the present invention in either sesame or peanut oil or in aqueous
propylene glycol may be employed. The aqueous solutions should be
suitably buffered (preferably pH greater than 8) if necessary and
the liquid diluent first rendered isotonic. These aqueous solutions
are suitable for intravenous injection purposes. The oily solutions
are suitable for intraarticular, intramuscular and subcutaneous
injection purposes. The preparation of all these solutions under
sterile conditions is readily accomplished by standard
pharmaceutical techniques well known to those skilled in the
art.
Additionally, it is also possible to administer the active
compounds of the present invention topically when treating
inflammatory conditions of the skin and this may be done by way of
creams, jellies, gels, pastes, patches, ointments and the like, in
accordance with standard pharmaceutical practice.
The ability of compounds cof the formulae I to inhibit NOS may be
determined using procedures described in the literature. The
ability of compounds of the formulae I to inhibit endothelial NOS
may be determined by using the procedures described by Schmidt et
al. in Proc. Natl. Acad. Sci. U.S.A., 88, pp. 365-369 (1991) and by
Pollock et al., in Proc. Natl. Acad. Sci. U.S.A., 88, pp.
10480-10484 (1991). The ability of compounds of the formulae I to
inhibit inducible NOS may be determined using the procedures
described by Schmidt et al., in Proc. Natl. Acad. Sci. U.S.A., 88
pp. 365-369 (1991) and by Garvey et al. in J. Biol. Chem., 269, pp.
26669-26676 (1994). The ability of the compounds of the formula I
to inhibit neuronal NOS may be determined using the procedure
described by Bredt and Synder in Proc. Natl. Acad. Sci. U.S.A., 87,
682-685 (1990).
Of 100 compounds of the formula I that were tested, all exhibited
an IC.sub.50 <10 .mu.M for inhibition of either inducible or
neuronal NOS.
The present invention is illustrated by the following examples. It
will be understood, however, that the invention is not limited to
the specific details of these examples. Melting points are
uncorrected. Proton nuclear magnetic resonance spectra (.sup.1 H
NMR) and C.sup.13 nuclear magnetic resonance spectra were measured
for solutions in deuterochloroform (CDCl.sub.3) or in CD.sub.3 OD
or CD.sub.3 SOCD.sub.3 and peak positions are expressed in parts
per million (ppm) downfield from tetramethylsilane (TMS). The peak
shapes are denoted as folloys: s, singlet; d, doublet; t, triplet;
q, quartet, m, multiplet, b, broad.
EXAMPLE 1
6-{4-[2-(4-Phenethyl-piperazin-1-yl)-ethyl]-phenyl}-pyridin-2-ylamine
A. 2-Amino-6-bromopyridine
In a 300 mL bomb were placed 40 g(168 mmol) 2,6-dibromopyridine and
125 mL 30% aqueous ammonium hydroxide, and the bomb sealed and
heated at 170.degree. C., 400 psi, for 3 hours. After cooling, the
contents were extracted into ethyl acetate, washed with brine and
dried over sodium sulfate. Then the solvent was evaporated. The
residue was chromatographed on silica gel using 2% methanol in
methylene chloride as eluant to afford 19.5 g(67%) or a light
yellow solid.
.sup.1 H-NMR (CDCl.sub.3,d): 106.8, 116.8, 139.9, 158.8. MS (%):
173/175 (parent, B.sup.79 /Br.sup.81, 100/98).
B. 2-Bromo-6-(2,5-dimethylpyrrol-1-yl)pyridine
To a 1 L round-bottomed flask equipped with Dean-Stark trap,
condenser, and nitrogen inlet were added 21.3 g(123 mmol)
2-amino-6-bromopyridine, 400 mL toluene, 14.1 g(123 mmol)
acetonylacetone, and 20 drops acetic acid. The reaction was
refluxed 5 days (tlc in 1/1:ethyl acetate/hexane, R.sub.f =0.8
(product), 0.5 (starting material)), cooled, poured into ethyl
acetate, washed with saturated aqueous sodium bicarbonate solution
and brine, dried over sodium sulfate, and evaporated. The residue
was chromatographed on silica gel using 5% methanol in methylene
chloride to afford 14.4 g(47%) of the product as a low-melting
yellow solid.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 2.16 (s, 6H), 5.89 (s, 2H),
7.17 (d, J-7, 1H), 7.47 (d, J=7, 1H), 7.67 (t, J=8, 1H). .sup.13
C-NMR (CDCl.sub.3, .delta.): 13.3, 107.6, 120.3, 126.4, 128.7,
139.8, 140.6, 151.9. MS (%): 251/253 (parent, Br.sup.79 Br.sup.81,
100/98).
C. 2-(4-Iodophenyl)ethanol)
To a 500 mL 3-neck round-bottomed flask equipped with dropping
funnel and nitrogen inlet were added 20.5 g (150 mmol)
2-(4-aminophenyl)ethanol and 100 mL hot water to give a solution A
solution of 3.5 mL concentrated sulfuric acid in 10 mL water was
added dropwise, and the solution cooled to 4.degree. C. A solution
of 13.5 mL concentrated sulfuric acid in 50 mL water was added
dropwise while maintaining the temperature between 0.degree. C. and
5.degree. C., then a solution of 13 g (188 mmol) sodium nitrite in
50 mL water was added dropwise at the same temperature. After
stirring 30 min at 0-5.degree. C., a solution of 85 g (512 mmol)
potassium iodide in 100 mL water was added dropwise, and the
reaction was allowed to warm to room temperature and stirred for 2
hour. The reaction was then heated to 60.degree. C. for 30 min,
cooled to room temperature, and extracted into ethyl acetate
(2.times.250 mL). The ethyl acetate layer was washed with aqueous
sodium thiosulfate solution and brine, dried over sodium sulfate,
and evaporated. The residue was chromatographed on silica gel using
20% and 50% ethyl acetate in hexane as eluant to afford 30.7 g
(82.5%) of the product as a light yellow solid.
.sup.1 H-NMR (CDCl, .delta.): 2.74 (m, 2H), 3.79 (m, 2H), 6.93 (m,
2H), 7.57 (m, 2H). .sup.13 C-NMR (CDCl.sub.3, .delta.): 38.6, 63.3,
91.7, 131.1, 137.6, 138.3. MS(%): 247 (parent, 23).
D. 2-(4-Iodophenyl)ethylchloride
To a 500 mL round-bottomed flask equipped with dropping funnel,
condenser and N.sub.2 inlet were added 307 g (124 mmol)
2-(4-iodophenyl)ethanol, 200 mL chloroform, and 10.0 mL (124 mmol)
pyridine. A solution of 13.5 mL (186 mmol) thionyl chloride in 50
mL chloroform was added dropwise over 15 min, and the reaction then
heated at reflux for 2 hr. The reaction was cooled, the solvent
evaporated, and the residue taken up in ethyl acetate, washed with
1 N hydrochloric acid, water, saturated aqueous sodium bicarbonate
solution and brine, dried, and evaporated. The resulting oil was
chromatographed on silica gel using 20% ethyl acetate in hexane as
eluant to afford 32.6 g (99%) of the product as an oil.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 3.00 (t, J=7, 2H), 3.68 (t,
J=7, 2H), 6.99 (m, 2H), 7.63 (m, 2H). .sup.13 C-NMR (CDCl.sub.3,
.delta.): 38.6, 44.6, 92.3, 128.8, 130.9, 137.7.
E.
2-(2,5-Dimethylpyrrol-1-yl)-6-(4-(2-chloroethyl)phenyl)-pyridine
To a 1 L 3-neck round-bottomed flask equipped with addition funnel
and nitrogen inlet were added 10.0 g (40 mmol)
2-bromo-6-(2,5-dimethylpyrrol-1-yl)pyridine and 200 mL dry
tetrahydrofuran. The solution was cooled at -78.degree. C., and a
1.6 M solution of butyl lithium in hexane (25 mL, 40 mmol) was
added dropwise over 10 min. The reaction was stirred at -78.degree.
C. for 20 min, then a 1.0 M solution of zinc chloride in ether (100
mL, 100 mmol) was added dropwise over 40 min keeping the
temperature at -70.degree. C. The reaction was then allowed to warm
to room temperature, and 11.0 g (40 mmol)
2-(4-iodophenyl)ethylchloride was added, followed by 200 mg
tetrakistriphenylphosphine palladium. The reaction was refluxed for
3 hours, cooled, and filtered through Celite. The filtrate was
evaporated, and the residue taken up in ethyl acetate, washed with
brine, dried over sodium sulfate, and evaporated. The residue was
filtered through silica gel with methylene chloride, concentrated,
and chromatographed on silica gel using 1% ethyl acetate in hexane
as eluant to afford 7.3 g (59%) of the product as an oil.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 2.19 (s, 6H), 3.10 (t, J=7,
2H), 3.73 (t, J-7, 2H), 5.91 (s, 2H), 7.12 (d, J=7, 1H), 7.32 (d,
J=8, 2H), 7.72 (m, 1H), 7.82 (m, 1H), 8.01 (m, 2H). .sup.13 C-NMR
(CDCl.sub.3, .delta.): 13.5, 28.9, 44.7, 106.9, 118.1, 119.8,
127.1, 128.7, 129.3, 137.1, 138.6, 139.4, 151.7, 156.6. MS (%): 311
(parent+1, 100).
F. 6-(4-(2-chloroethyl)phenyl)-pyridin-2-ylamine hydrochloride
To a 500 mL round-bottomed flask equipped with condenser and
nitrogen inlet were added 9.0 g (29.0 mmol)
2-(2,5-dimethylpyrrol-1-yl)-6-(4-(2-chloroethyl)phenyl)-pyridine,
250 mL ethanol, 50 mL water, and 10.1 g (145 mmol) hydroxylamine
hydrochloride. The reaction was refluxed for 36 hours, cooled, and
the solvent was evaporated. The residue was taken up in ethyl
acetate, washed with saturated aqueous sodium bicarbonate solution
and brine, dried over sodium sulfate, and evaporated. The residue
was chromatographed on silica gel using 2% methanol in methylene
chloride as eluant to afford 7.8 g (88%) of the product as a light
brown solid.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 2.97 (broad s, 2H, NH.sub.2),
3.05 (t, J=7, 2H), 3.68 (t, J=7, 2H), 6.85 (m, 1H), 6.88 (m, 1H),
7.33 (m, 2H), 7.68 (6, J=7, 1H), 7.78 (m, 2H). MS (%): 232 (parent,
60), 183 (100).
G.
6-{4-[2-(4-Phenethyl-piperazin-1-yl)-ethyl]-phenyl}-pyridin-2-ylamine
To a 50 mL round-bottomed flask equipped with condenser and N.sub.2
inlet were added 20 mg (0.65 mmol)
6-(4-(2-chloroethyl)phenyl)-pyridin-2-ylamine hydrochloride, 125
mg(0.98 mmol) diisopropylethylamine, 208 mg (1.9 mmol) sodium
carbonate, and 5 mL dry dimethylformamide. The reaction was heated
at reflux for 18 hours, cooled, and poured into water, then
extracted into ethyl acetate. The organic layer was extracted into
1 N hydrochloric acid, after which the aqueous layer washed with
fresh ethyl acetate, basified with 1 N aqueous sodium hydroxide
solution, and then extracted into ethyl acetate. The organic layer
was washed with brine, dried over sodium sulfate, and evaporated.
The residue was chromatographed on silica gel using 2% and 5%
methanol in methylene chloride as eluant to afford 71 mg (28%) of
the product as a tan solid mp 111-113.degree. C.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 2.64 (m, 6H), 2.84 (m, 2H),
4.52 (broad s, 2H), 6.41 (d, J=8, 1H), 7.04 (d, J=7, 1H), 7.1-7.3
(m, 7H), 7.45 (t, J=8, 1H), 7.84 (m, 2H). .sup.13 C-NMR
(CDCl.sub.3, .delta.): 33.3, 33.6, 53.2, 60.3, 60.5, 106.9, 110.7,
126.1, 126.8, 128.4, 128.7, 128.9, 137.6, 138.3, 140.3, 140.9,
156.1, 158.2. MS (%): 387 (parent+1, 100). Anal. Calc'd for
C.sub.25 H.sub.30 N.sub.4.1/2H.sub.2 O: C, 75.91, H, 7.90, N,
14.16. Found: C, 76.00, H, 8.01, N, 14.17.
EXAMPLE 2
6-((2-(6-(t-butoxycarbonylamino)-3-azabicyclo[3.1.
0]hex-3-yl)ethyl)phenyl)-pyridin-2-ylamine
The title compound was prepared using the procedure described in
Example 1G using
6-(t-butoxycarbonylamino)-3-aza-bicyclo[3.1.0]hexane, in 48% yield
as a brown oil.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 1.43 (s, 9H), 1.50 (m, 1H),
1.70 (m, 1H), 2.40 (m, 1H), 2.64 (m, 1H), 2.75 (m, 1H), 3.15 (m,
1H), 4.46 (m, 1H), 6.42 (d, J=8, 1H), 7.05 (d, J=7, 1H), 7.22 (m,
2H), 7.47 (t, J=8, 1H), 7.81 (d, J=8, 1H). .sup.13 C-NMR
(CDCl.sub.3, .delta.): 28.4, 31.4, 35.2, 36.4, 54.5, 56.9, 79.4,
106.8, 110.75, 126.7, 128.8, 137.4, 138.3, 141.1, 156.1, 158.2,
162.5. MS (%): 395 (parent, 100).
3-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-3-aza-bicyclo[3.1.
0]hex-6-ylamine
To a 25 mL round-bottomed flask equipped with nitrogen inlet were
added 135 mg (0.342 mmol)
6-((2-(6-(t-butoxycarbonylamino)-3-azabicyclo[3.1.
0]hex-3-yl)ethyl)phenyl)-pyridin-2-ylamine, 10 mL methylene
chloride, and 3 mL trifluoroacetic acid. After stirring 30 min at
room temperature, the reaction was evaporated and the residue
triturated with tetrahydrofuran and ethyl ether to afford 195 mg
(76%) of a yellowish solid, mp 187-190.degree. C.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 2.33 (m, 2H), 2.95 (m, 1H),
3.10 (m, 3H), 3.47 (m, 2H), 3.6-4.0 (m, 2H), 6.95 (d, J=8, 1H),
7.13 (d, J=7, 1H), 7.49 (m, 2H), 7.76 (m, 2H), 7.94 (t, J=7, 1H).
.sup.13 C-NMR (free base in CDCl.sub.3, .delta.): 25.8, 32.7, 35.2,
55.0, 57.3, 106.8, 110.8, 126.7, 128.9, 137.5, 138.3, 141.0, 156.1,
158.2. MS (%): 295 (parent+1, 100). Anal. Calc'd for C.sub.18
H.sub.22 N.sub.4.3(C.sub.2 HF.sub.3 O.sub.2): C, 45.29, H, 3.96, N,
8.80. Found: C, 45.30, H, 3.93, N, 8.80.
EXAMPLE 3
1-(4-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-piperazin-1-yl)-2-phenyl-e
thanone
A.
6-((2-(4-(t-butoxycarbonyl)piperazin-1-yl)ethyl)phenyl)-pyridin-2-ylamine
The title compound was prepared using the procedure described in
Example 1G using t-butoxycarbonylpiperazine in 57.5% yield with
methylisobutylketone as solvent at reflux for 5 days as a light
brown solid.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 1.45 (s, 9H), 2.46 (m, 4H),
2.61 (m, 2H), 2.84 (m, 2H), 3.45 (m, 4H) 4.48 (broad, s, 2H), 6.42
(d, J=8, 1H), 7.05 (d, J=7, 1H), 7.25 (m, 2H), 7.47 (t, J=8, 1H),
7.84 (m, 2H). .sup.13 C-NMR (CDCl.sub.3, .delta.): 28.4, 33.3,
53.0, 60.3, 106.9, 110.7, 126.8, 128.9, 137.7, 138.3, 140.7, 154.8,
156.0, 158.2. MS (%): 383 (parent+1, 14), 283 (70), 197 (72), 143
(70), 99 (100).
B. 6-((2(piperazin-1-yl)ethyl)phenyl)-pyridin-2-ylamine:
The title compound was prepared using the procedure described in
Example 2B in 94% yield as a light brown solid.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 1.69 (s, 1H), 2.49 (broad s,
4H), 2.58 (m, 2H), 2.85 (m, 2H), 2.91 (m, 4H), 4.49 (broad s, 2H),
6.41 (d, J=8, 1H), 7.04 (d, J=7, 1H), 7.26 (m, 2H), 7.46 (t, J=8,
1H), 7.84 (m, 2H). .sup.13 C-NMR (CDCl.sub.3, .delta.): 33.1, 46.1,
54.5, 61.0, 106.8, 110.7, 126.8, 128.9, 137.6, 138.3, 140.9, 156.1,
156.2. MS (%): 283 (parent, 100).
C.
1-(4-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-piperazin-1-yl)-2-phenyl-
ethanone
To a 50 mL round-bottomed flask equipped with nitrogen inlet were
added 150 mg (0.53 mmol)
6-((2-(piperazin-1-yl)ethyl)phenyl)-pyridin-2-ylamine, 15 mL
methylene chloride, 0.070 mL (0.53 mmol) triethylamine, and 0.070
mL (0.53 mmol) phenylacetyl chloride. The reaction was stirred 1
hour at room temperature. The residue was chromatographed on silica
gel using 2.5% methanol in methylene chloride to afford 126 mg
(59%) of the product as a tan solid, mp 135-137.degree. C.
.sup.1 H-NMR CDCl.sub.3, .delta.): 2.31 (m, 2H), 2.48 (m, 2H), 2.60
(m, 2H), 2.79 (m, 2H), 3.45 (m, 2H), 3.67 (m, 2H), 3.73) s, 2H),
4.53 (broad s, 2H), 6.42 (d, J-8, 1H) 7.03 (d, J=7, 1H), 7.2-7.4
(m, 7H), 7.47 (t, J=8, 1H), 7.82 (m, 2H). .sup.13 C-NMR
(CDCl.sub.3, .delta.): 33.1, 41.0, 41.7, 46.0, 52.6, 53.0, 59.9,
107.0, 110.7, 126.8, 126.9, 128.6, 128.7, 128.9, 135.1, 137.6,
138.4, 140.5, 155.9, 158.2, 169.4. MS (%): 401 (parent+1, 100).
Anal. Calc'd for C.sub.25 H.sub.28 N.sub.4 O.1/4H.sub.2 O: C,
74.14, H, 7.04, N, 13.83. Found: C, 74.48, H, 7.05, N, 13.86.
EXAMPLE 4
4-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-piperazine-1-carboxylic
Acid phenylamide
To a 50 mL round-bottomed flask equipped with nitrogen inlet were
added 150 mg (0.53 mmol)
6-((2-(piperazin-1-yl)ethyl)phenyl)-pyridin-2-ylamine, 60 uL (0.53
mmol) phenylisocyanate, 10 mL 1,2-dichloroethane, 10 mL ethyl
acetate, and 64 mg (0.53 mmol) 4-dimethylaminopyridine. The
reaction was stirred at room temperature for 14 hours, evaporated,
and chromatographed on silica gel using 5% methanol in methylene
chloride as eluant to afford 205 mg (96%) of the product as a foam,
mp 60.degree. C.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 2.55 (m, 4H), 2.68 (m, 2H),
2.85 (m, 2H), 3.52 (m, 4H), 4.49 (broad s, 2H), 6.39 (s, 1H), 6.42
(d, J=8, 1H), 7.0-7.4 (m, 7H), 7.48 (t, J=8, 1H), 7.86 (m, 2H).
.sup.13 C-NMR (CDCl.sub.3, .delta.): 33.3, 44.1, 52.8, 60.1, 106.9,
110.8, 119.9, 123.1, 126.9, 128.9, 137.7, 138.4, 139.0, 140.6,
155.0, 156.0, 158.2. MS (%): 402 (parent+1, 100). Anal. Calc'd for
C.sub.24 H.sub.27 N.sub.5 O.1/2H.sub.2 O: C, 70.22, H, 6.88, N,
17.06. Found: C, 70.27, H, 6.60, N, 17.22.
EXAMPLE 5
1-(4-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-piperazin-1-yl)-2-(4-fluor
o-phenyl)-ethanone
To a 50 mL round-bottomed flask equipped with nitrogen inlet were
added 200 mg (0.71 mmol)
6-((2-(piperazin-1-yl)ethyl)phenyl)-pyridin-2-ylamine, 10 mL dry
dimethyformamide, 109 mg (0.71 mmol) 4-fluorophenylacetic acid, 204
mg (1.1 mmol) ethyl(3-dimethylaminoproryl)carbodiimide, and 0.36 mL
(2.1 mmol) diisopropylethylamine. The reaction was stirred at room
temperature for 18 hours, poured into water and extracted into
ethyl acetate. The organic layer was extracted into 1 N
hydrochloric acid, the aqueous layer washed with fresh ethyl
acetate, and the aqueous layer basified with 1 N aqueous sodium
hydroxide solution and extracted into ethyl acetate. The organic
layer was washed with brine, dried over sodium sulfate, and
evaporated. The residue was chromatographed on silica gel using 3%
methanol in methylene chloride to afford 100 mg (34%) of the
product as a tan solid, mp 143-145.degree. C.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 2.34 (m, 2H), 2.46 (m, 2H),
2.60 (m, 2H), 2.79 (m, 2H), 3.45 (m, 2H), 3.66 (m, 2H), 3.67 (s,
2H), 4.52 (broad s, 2H), 6.41 (d, J=8, 1H), 6.9-7.3 (m, 6H), 7.46
(t, J=8, 11H), 7.82 (m, 2H). .sup.13 C-NMR (CDCl.sub.3, .delta.):
33.2, 39.9, 41.8, 46.0, 52.7, 53.1, 59.9, 106.9, 110.7, 115.4,
115.7, 126.8, 128.9, 130.2, 130.3, 130.7, 130.8, 137.7, 138.3,
140.5, 155.9, 158.2, 160.1, 163.4, 169.2. MS (%): 419 (parent+1,
100). Anal. Calc'd for C.sub.25 H.sub.27 FN.sub.4 O: C, 71.75, H
6.50, N, 13.39. Found: C, 71.46, H, 6.68, N, 13.39.
EXAMPLE 6
6-{4-[2-(3,4-Dihydro-1H-isoquinolin-2-yl)-ethyl]-phenyl}-pyridin-2-ylamine
Prepared as in Example 1, using 1,2,3,4-tetrahydroisoquinoline, in
51% yield, mp 130-132.degree. C.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 2.8-3.0 (m, 8H), 3.76 (bs, 2H),
6.39 (d, J=8, 1H), 7.0-7.3 (m, 7H), 7.46 (t, J=8, 1H), 7.87 (d,
J=8, 2H). .sup.13 C-NMR (CDCl.sub.3, .delta.): 29.0, 33.6, 50.9,
55.9, 60.0, 107.0, 110.7, 125.7, 126.2, 126.7, 127.0, 128.7, 129.0,
134.2, 134.5, 137.7, 138.4, 140.9, 156.0, 158.4. MS (%): 330
(parent+1, 100). Anal. Calc'd. for C.sub.22 H.sub.23 N.sub.3 : C,
80.21, H, 7.04, N, 12.75. Found: C, 80.05, H, 7.11, N, 12.62.
EXAMPLE 7
(4-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-piperazin-1-yl)-furan-2-yl-m
ethanone
Prepared as in Example 1, using (2-furoyl)piperazine, in 51% yield,
mp 152-154.degree. C.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 2.55 (m, 2H), 2.65 (m, 2H),
2.82 (m, 2H), 3.81 (bs, 2H), 4.55 (bs, 2H), 6.44 (m, 2H), 6.96 (m,
1H), 7.02 (d, J=8, 1H), 7.23 (m, 2H), 7.45 (m, 2H), 7.83 (m, 2H).
.sup.13 C-NMR (CDCl.sub.3, .delta.): 33.2, 53.2 (broad), 60.0,
106.9, 110.6, 111.2, 126.9, 128.9, 137.7, 138.3, 140.6, 143.6,
148.0, 155.9, 158.3, 159.1. MS (%): 377 (parent+1, 100). Anal.
Calc'd. for C.sub.22 H.sub.24 N.sub.4 O.sub.2.3/4H.sub.2 O: C,
67.76, H, 6.59, N, 14.37. Found: C, 67.65, H, 6.25, N, 14.44.
EXAMPLE 8
6-{4-[2-(4-m-Tolyl-piperazin-1-yl)-ethyl]-phenyl}-pyridin-2-ylamine
Prepared as in Example 1, using (3-tolyl)piperazine, in 60% yield,
mp 158-160.degree. C.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 2.32 (s, 3H), 2.69 (m, 4H),
2.89 (m, 2H), 3.23 (m, 4H), 4.52 (bs, 2H), 6.43 (d, J=8, 1H),
6.6-6.8 (m, 3H), 7.07 (d, J=8, 1H), 7.16 (m, 1H), 7.29 (m, 2H),
7.48 (t, J=8, 1H), 7.86 (m, 2H). .sup.13 C-NMR (CDCl.sub.3,
.delta.): 21.8, 33.4, 49.2, 53.3, 60.3, 106.9, 110.7, 113.2, 116.9,
120.6, 126.9, 128.9, 137.7, 138.3, 138.8, 140.8, 151.4, 156.0,
158.2. MS (%): 373 (parent+1). Anal. Calc'd. for C.sub.24 H.sub.28
N.sub.4.1/4H.sub.2 O: C, 76.46, H, 7.62, N, 14.86. Found: C, 76.45,
H, 7.43, N, 14.66.
EXAMPLE 9
6-(4-{2-[4-(3-Trifluoromethyl-phenyl)-piperazin-1-yl]-ethyl}-phenyl)-pyridi
n-2-ylamine
Prepared as in Example 1, using
(3-trifluoromethylphenyl)piperazine, in 62% yield, mp 189-191
.degree. C.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 2.68 (m, 4H), 2.88 (m, 2H),
3.26 (m, 4H), 4.51 (bs, 2H), 6.43 (d, J=8, 1H), 7.0-7.4 (m, 7H),
7.47 (t, J=8, 1H), 7.86 (m, 2H). .sup.13 C-NMR (CDCl.sub.3,
.delta.): 33.4, 48.7, 53.0, 60.2, 106.9, 110.7, 112.0, 112.1,
115.7, 115.8, 118.6, 122.5, 126.2, 126.9, 128.9, 129.5, 131.2,
131.6, 137.7, 138.3, 140.7, 151.4, 156.0, 158.2. MS (%): 427
(parent+1, 41). Anal. Calc'd. for C.sub.24 H.sub.25 F.sub.3 N.sub.4
: C, 67.59, H, 5.91, N, 13.14. Found: C, 67.30, H, 5.95, N,
13.28.
EXAMPLE 10
1-(4-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-piperazin-1-yl)-ethanone
Prepared as in Example 1, using N-acetylpiperazine, in 47% yield,
mp 201-203.degree. C.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 2.08 (s, 3H), 2.49 (m, 4H),
2.62 (m, 2H), 2.82 (m, 2H), 3.47 (m, 2H), 3.64 (m, 2H), 4.47 (bs,
2H), 6.43 (d, J=8, 1H), 7.05 (d, J=8, 1H), 7.1-7.2 (m, 2H), 7.47
(t, J=8, 1H), 7.84 (m, 2H). .sup.13 C-NMR (CDCl.sub.3, .delta.):
21.3, 33.3, 41.4, 46.3, 52.7, 53.3, 60.1, 106.9, 110.7, 126.9,
128.9, 137.7, 138.3, 140.6, 156.0, 158.2, 168.9. MS (%): 325
(parent+1, 100). Anal. Calc'd. for C.sub.19 H.sub.24 N.sub.4 O: C,
70.34, H, 7.46, N, 17.27. Found: C, 70.21, H, 7.77, N, 17.10.
EXAMPLE 11
1-(4-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-1-piperazin-1-yl)-2-methox
y-ethanone
Prepared as in Example 1, using 4-(2-methoxyacetyl)piperazine, in
53% yield, mp 148-150.degree. C.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 2.49 (m, 4H), 2.61 (m, 2H),
2.83 (m, 2H), 3.40 (s, 3H), 3.48 (m, 2H), 3.65 (m, 2H), 4.08 (s,
2H), 4.53 (bs, 2H), 6.41 (d, J=8, 1H), 7.03 (d, J=7, 1H), 7.24 (m,
2H), 7.46 (t, J=8, 1H), 7.83 (m, 2H). .sup.13 C-NMR (CDCl.sub.3,
.delta.): 33.2, 41.8, 44.9, 52.8, 53.4, 59.0, 60.0, 71.8, 106.9,
110.7, 126.9, 128.9, 137.7, 138.3, 140.5, 155.9, 158.3, 167.4. MS
(%): 355 (parent+1, 100). Anal. Calc'd. for C.sub.20 H.sub.26
N.sub.4 O.sub.2 : C, 67.77, H, 7.39, N, 15.81. Found: C, 67.80, H,
7.66, N, 15.79.
EXAMPLE 12
1-(4-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-piperazin-1-yl)-2-phenoxy-
ethanone
Prepared as in Example 1, using 4-(2-phenoxyacetyl)piperazine, in
57.5% yield, mp 127-130.degree. C.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 2.49 (m, 4H), 2.60 (m, 2H),
2.81 (m, 2H), 3.59 (m, 2H), 3.65 (m, 2H), 4.51 (bs, 2H), 4.68 (s,
2H), 6.43 (d, J=8, 1H), 6.8-7.0 (m, 3H), 7.05 (d, J=8, 1H), 7.2-7.4
(m, 4H), 7.47 (t, J=8, 1H), 7.83 (m, 2H). .sup.13 C-NMR
(CDCl.sub.3, .delta.): 33.2, 42.1, 45.4, 52.7, 53.3, 60.0, 67.7,
106.9, 110.7, 114.6, 121.7, 126.9, 128.9, 129.6, 137.7, 138.3,
140.5, 155.9, 157.8, 158.2, 166.4. MS (%): 417 (parent+1, 100).
Anal. Calc'd. for C.sub.25 H.sub.28 N.sub.4 O.sub.2.1/4H.sub.2 O:
C, 71.32, H, 6.82, N, 13.31. Found: C, 71.55, H, 6.93, N,
13.25.
EXAMPLE 13
(4-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-piperazin-1-yl)-cyclopentyl-
ethanone
Prepared as in Example 1, using 4-(cyclopentanecarbonyl)piperazine,
in 3.5% yield, mp 185-187.degree. C.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 1.55 (m, 2H), 1.74 (m, 2H),
1.79 (m, 4H), 2.48 (m, 4H), 2.63 (m, 2H), 2.83 (m, 3H), 3.53 (m,
2H), 3.65 (m, 2H), 4.51 (bs, 2H), 6.42 (d, J=8, 1H), 7.03 (d, J=7,
1H), 7.25 (m, 2H), 7.46 (t, J=8, 1H), 7.83 (m, 2H). .sup.13 C-NMR
(CDCl.sub.3, .delta.): 26.0, 30.1, 33.3, 41.0, 41.8, 45.5, 52.9,
53.6, 60.1, 106.9, 110.7, 126.9, 128.9, 137.7, 138.3, 140.6, 156.0,
158.2, 174.5. MS (%): 379 (parent+1, 100). Anal. Calc'd. for
C.sub.23 H.sub.30 N.sub.4 O.3/4H.sub.2 O: C, 70.47, H, 8.10, N,
14.29. Found: C, 70.40, H, 7.91, N, 14.02.
EXAMPLE 14
6-{4-[2-(5-Methyl-2,5-diaza-bicyclo[2.2.
1]hept-2-yl)-ethyl]-phenyl}-pyridin-2-ylamine
Prepared as in Example 1, using
5-methyl-2,5-diazabicyclo[3.3.1]heptane, in 29% yield, mp
132.degree. C. (dec.) as the hydrochloride salt.
FAB MS (%): 309 (parent, 4), 279 (7), 167 (18), 149 (100), 113
(19). Anal. Calc'd. for C.sub.19 H.sub.24 N.sub.4.3HCl: C, 53.34,
H, 6.83, N, 13.10. Found: C, 15 53.61, H, 6.94, N, 12.05.
EXAMPLE 15
6-(4-{2-[4-(4-Phenyl-thiazol-2-yl)-piperazin-1-yl]-ethyl}-phenyl)-pyridin-2
-ylamine
Prepared as in Example 1, using N-(4-phenyl-2-thiazolyl)piperazine,
in 30% yield, mp 158-161.degree. C.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 2.65 (m, 4H), 2.87 (m, 2H),
3.58 (m, 6H), 4.50 (bs, 2H), 6.42 (d, J=8, 1H), 6.76 (s, 1H), 7.04
(d, J=7, 1H), 7.2-7.4 (m, 5H), 7.47 (d, J=8, 1H), 7.85 (m, 4H).
.sup.13 C-NMR (CDCl.sub.3, .delta.): 33.3, 48.4, 52.4, 60.2, 101.5,
107.0, 110.7, 126.1, 126.9, 127.6, 128.5, 128.9, 129.3, 135.1,
137.6, 138.4, 140.6, 151.9, 155.9, 158.2, 160.9, 171.0. MS (%): 442
(parent+1, 100). Anal. Calc'd. for C.sub.25 H.sub.27 N.sub.5
S.1/4H.sub.2 O: C, 70.02, H, 6.21, N, 15.70. Found: C, 69.92, H,
6.18, N, 15.31.
EXAMPLE 16
2-(4-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-piperazin-1-yl)-1-phenyl-e
thanone
Prepared as in Example 1, using N-(benzoylmethyl)piperazine, in 66%
yield, mp 225.degree. C. (dec.) as the hydrochloride salt.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 2.8-3.2 (m, 10H), 3.56 (m, 2H),
3.88 (s, 2H), 6.48 (m, 1H), 6.99 (m, 1H), 7.2-7.6 (m, 6H), 7.82 (m,
2H), 7.93 (m, 2H). .sup.13 C-NMR (CDCl.sub.3, .delta.): 31.6, 42.4,
51.7, 52.6, 54.1, 59.2, 63.6, 107.6, 110.6, 127.1, 128.0, 128.7,
129.0, 129.6, 133.5, 135.7, 137.2, 138.9, 139.1, 154.8, 158.1,
170.5. MS (%): 401 (parent+1, 100). Anal. Calc'd. for C.sub.25
H.sub.28 N.sub.4 O.3HCl.3H.sub.2 O: C, 53.24, H, 6.61, N, 9.93.
Found: C, 53.39, H, 6.21, N, 10.06.
EXAMPLE 17
6-{4-[2-(4-Isobutyl-piperazin-1-yl)-ethyl]-phenyl}-pyridin-2-ylamine
Prepared as in Example 1, using N-isobutylpiperazine, in 44.5%
yield, mp 85-88.degree. C.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 0.88 (d, J=7, 6H), 1.77 (m,
1H), 2.11 (d, J=7, 2H), 2.5-2.7 (m, 10H), 2.83 (m, 2H), 4.49 (bs,
2H), 6.40 (d, J=8, 1H), 7.03 (d, J=7.5, 1H), 7.24 (m, 2H), 7.45 (t,
J=8, 1H), 7.82 (m, 2H). .sup.13 C-NMR (CDCl.sub.3, .delta.): 20.9,
25.3, 33.2, 53.0, 53.3, 60.2, 66.7, 106.9, 110.7, 126.9, 128.9,
137.65, 138.4, 140.7, 156.0, 158.3. MS (%): 339 (parent+1, 42).
Anal. Calc'd. for C.sub.21 H.sub.30 N.sub.4.1/2H.sub.2 O: C, 72.58,
H, 8.99, N, 16.12. Found: C, 72.98, H, 9.12, N, 16.44.
EXAMPLE 18
6-{4-[2-(1,2,3,4-Tetrahydro-naphthalen-2-ylamino)-ethyl]-phenyl}-pyridin-2-
ylamine
Prepared as in Example 1, using 2-aminotetralin, in 18% yield, mp
320-322.degree. C. as the hydrochloride salt.
.sup.1 H-NMR (CD.sub.3 OD, .delta.) hydrochloride salt: 1.8-2.0 (m,
2H), 2.4-2.5 (m, 4H), 2.9-3.0 (m, 2H), 3.1-3.2 (m, 3H), 6;.99 (d,
J=8, 1H), 7.1-7.2 (m, 5H), 7.59 (m, 2H), 7.83 (m, 2H), 7.9-8.0 (m,
1H). .sup.13 C-NMR (CDCl.sub.3, .delta.): 15.5, 27.2, 28.4, 33.2,
56.2, 66.9, 112.0, 112.9, 127.5, 127.9, 128.8, 129.8, 130.3, 131.2,
133.0, 136.0, 141.7, 145.9. MS (%): 344 (parent+1, 100). Anal.
Calc'd. for C.sub.23 H.sub.25 N.sub.3.2HCl.1/2H.sub.2 O: C, 64.94,
H, 6.63, N, 9.88. Found: C, 64.87, H, 6.83, N, 9.86.
EXAMPLE 19
6-(Dibenzylamino)ethyl)phenyl)-pyridin-2-ylamine
Prepared as in Example 1, using dibenzylamine, in 14% yield, mp
206-208.degree. C. as the hydrochloride salt.
.sup.1 H-NMR (CD.sub.3 OD, .delta.) hydrochloride salt: 2.91 (t,
J=7, 2H), 3.80 (t, J=7, 2H), 4.24 (bs, 4H), 6.97 (d, J=8, 1H), 7.15
(d, J=7, 1H), 7.4-7.5 (m, 12H), 7.74 (m, 2H), 7.97 (dd, J=7,8, 1H).
.sup.13 C-NMR (CDC.sub.3, .delta.): 39.9, 52.1, 63.6, 111.8, 112.5,
128.2, 130.3, 130.7, 130.9, 131.1, 131.3, 132.4, 144.8, 145.9,
148.5, 156.7. MS (%): 309 (4), 215 (25), 198 (100), 155 (22), 135
(13), 119 (47), 103 (21). Anal. Calc'd. for C.sub.27 H.sub.27
N.sub.3.3HCl: C, 64.48, H, 6.01, N, 8.36. Found: C, 64.84, H, 6.31,
N, 9.07.
EXAMPLE 20
6-{4-[2-(8-Aza-spiro[4.5]dec-8-yl)-ethyl]-phenyl}-pyridin-2-ylamine
Prepared as in Example 1, using 8-Aza-spiro[4.5]decane, in 63%
yield, mp 130-132.degree. C.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 1.3-1.7 (m, 12H), 2.47 (bs,
4H), 2.59 (m, 2H), 2.86 (m, 2H), 4.49 (bs, 2H), 6.42 (d, J=8, 1H),
7.04 (d, J=7.5, 1H), 7.2-7.3 (m, 2H), 7.46 (t, J=8, 1H), 7.83 (m,
2H). .sup.13 C-NMR (CDCl.sub.3, .delta.): 24.3, 33.5, 37.5, 38.0,
40.7, 51.5, 60.8, 106.8, 110.7, 126.8, 128.9, 137.6, 138.3, 141.1,
156.1, 158.2. MS (%): 336 (parent+1, 79). Anal. Calc'd. for
C.sub.22 H.sub.29 N.sub.3.1/4H.sub.2 O: C, 77.72, H, 8.75, N,
12.36. Found: C, 77.74, H, 8.74, N, 12.41.
EXAMPLE 21
6-{4-[2-(4-Dimethylamino-piperidin-1-yl)-ethyl]-phenyl}-pyridin-2-ylamine
Prepared as in Example 1, using 4-(N,N-dimethylamino)piperidine, in
60% yield, mp 174-176.degree. C.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 1.5-1.6 (m, 2H), 1.8 (m, 2H),
2.0 (m, 2H), 2.29 (s, 6H), 2.60 (m, 2H), 2.80 (m, 2H), 3.15 (m,
2H), 3.4-3.5 (m, 1H), 4.51 (bs, 2H, NH), 6.41 (d, J=8, 1H), 7.04
(d, J=7, 1H), 7.24 (m, 2H), 7.46 (t, J=8, 1H), 7.82 (m, 2H).
.sup.13 C-NMR (CDCl.sub.3, .delta.): 28.1, 33.6, 41.5, 53.1, 60.4,
62.3, 106.9, 110.7, 126.8, 128.9, 137.6, 138.3, 141.0, 156.1,
158.2. MS (%): 325 (parent+1, 100), 280 (45), 197 (65). Anal.
Calc'd. for C.sub.23 H.sub.25 N.sub.3.1/2H.sub.2 O: C, 72.03, H,
8.77, N, 16.80. Found: C, 72.09, H, 8.57, N, 16.86.
EXAMPLE 22
6-{4-[2-(1,3-Dihydro-isoindol-2-yl)-ethyl]-phenyl}-pyridin-2-ylamine
Prepared as in Example 1, using dihydroisoindole, in 19% yield, mp
140-143.degree. C.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 2.97 (m, 4H), 4.00 (bs, 4H),
4.51 (bs, 2H), NH), 6.42 (d, J=8, 1H), 7.06 (d, J=8, 1H), 7.20 (m,
4H), 7.32 (m, 2H), 7.47 (t, J=8, 1H), 7.86 (m, 2H). .sup.13 C-NMR
(CDCl.sub.3, .delta.): 35.5, 57.8, 59.2, 106.9, 110.8, 122.3,
126.7, 126.9, 128.9, 137.7, 138.3, 139.9, 140.8, 156.1, 158.2. MS
(%): 316 (parent+1, 92), 197 (43), 132 (100). Anal. Calc'd. for
C.sub.21 H.sub.21 N.sub.3.1/2H.sub.2 O: C, 77.75, H, 6.84, N,
12.95. Found: C, 78.03, H, 6.78, N, 12.58.
EXAMPLE 23
2-(4-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-piperazin-1-yl)-N-isopropy
l-acetamide
Prepared as in Example 1, using 4-(N-isopropylacetamido)piperazine,
in 78% yield, mp 163-165.degree. C.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 1.14 (d, J=6, 6H), 2.55 (m,
8H), 2.6 (m, 2H), 2.75 (m, 2H), 2.96 (s, 2H), 4.07 (hp, J=6, 1H),
4.52 (bs, 2H, NH), 6.42 (d, J=8, 1H), 6.92 (m, 1H), 7.03 (d, J=7,
1H), 7.24 (m, 2H), 7.46 (t, J=8, 1H), 7.82 (m, 2H). .sup.13 C-NMR
(CDCl.sub.3, .delta.): 22.8, 33.4, 40.7, 53.2, 53.4, 60.2, 61.6,
106.9, 110.7, 126.9, 128.9, 137.7, 138.3, 140.7, 156.0, 158.2,
169.1. MS (%): 382 (parent+1, 100), 198 (75). Anal. Calc'd. for
C.sub.22 H.sub.31 N.sub.5 O: C, 69.26, H, 8.19, N, 18.36. Found: C,
68.97, H, 8.36, N, 18.58.
EXAMPLE 24
(4-{2-[4-(6-Amino-pyridin-2-yl-)-phenyl]-ethyl}-piperazin-1-yl)-acetic
acid ethyl ester
Prepared as in Example 1, using 4-(N-carboethoxymethyl)piperazine,
in 16% yield, as a low-melting sold.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 1.26 (t, J=7, 3H), 2.5-2.7 (m,
10H), 2.83 (m, 2H), 3.20 (s, 2H), 4.17 (q, J=7, 2H), 4.49 (bs, 2H),
6.41 (d, J=8, 1H), 7.04 (d, J=7, 1H), 7.25 (m, 2H), 7.46 (t, J=7,
1H), 7.82 (m, 2H). .sup.13 C-NMR (CDCl.sub.3, .delta.): 14.25,
33.3, 52.9, 53.0, 59.6, 60.2, 60.6, 106.9, 110.7, 126.8, 128.9,
137.6, 138.3, 140.8, 156.0, 158.2, 170.3. IR (cm..sup.-1, KBr):
1740 (C.dbd.O). MS (%): 369 (parent+1, 100), 197 (35), 185 (70),
119 (38). HRMS (%): 369.23070 (parent+1, 100, calculated
369.22905).
EXAMPLE 25
(4-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-piperazin-1-yl)-phenyl-metha
none
Prepared as in Example 1, using (N-benzoyl)piperazine, in 43%
yield, mp 125-127.degree. C.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 2.4 (m, 2H), 2.5-2.7 (m, 4H),
2.85 (m, 2H), 3.5 (m, 2H), 3.8 (m, 2H), 4.53 (bs, 2H), NH), 6.41
(d, J=8, 1H), 7.03 (d, J=7, 1H), 7.24 (m, 2H), 7.38 (m, 5H), 7.45
(t, J=8, 1H), 7.83 (m, 2H). .sup.13 C-NMR (CDCl.sub.3, .delta.):
33.2, 60.1, 106.9, 110.7, 126.9, 127.1, 128.5, 128.9, 129.7, 135.8,
137.7, 138.3, 140.5, 155.9, 158.3, 170.3. MS (%): 387 (parent+1,
92), 203 (35), 105 (100). Anal. Calc'd. for C.sub.24 H.sub.26
N.sub.4 O.1/4H.sub.2 O: C, 73.72, H, 6.83, N, 14.33. Found: C,
73.96, H, 6.88, N, 14.39.
EXAMPLE 26
6-{4-[2-(3-Phenyl-pyrrolidin-1-yl)-ethyl]-phenyl}-pyridin-2-ylamine
Prepared as in Example 1, using 3-phenylpyrrolidine, in 54% yield,
mp 100.degree. C. (dec.) as the hydrochloride salt.
.sup.1 H-NMR as the hydrochloride salt (MeOD, .delta.): 2.2-2.6 (m,
2H), 3.2-3.4 (m, 5H), 3.5-3.7 (m, 2H), 3.7-4.0 (m, 2H), 6.99 (d,
J=8, 1H), 7.17 (d, J=7, 1H), 7.3-7.5 (m, 5H), 7.59 (m, 2H), 7.83
(m, 2H), 7.97 (t, J=8, 1H). .sup.13 C-NMR (CDCl.sub.3, .delta.):
(the aliphatic and some of the aromatic carbons are doubled,
possibly due to restricted rotation) 31.9, 32.7, 32.8, 34.2, 55.0,
56.5, 56.9, 57.5, 60.6, 60.9, 111.9, 112.9, 128.4, 128.6, 128.7,
128.9, 130.0, 131.2, 131.9, 139.8, 140.8, 141.6, 145.9, 147.8,
156.8. MS (%): 344 (parent+1, 100), 197 (26), 160 (40). Anal.
Calc'd. for C.sub.23 H.sub.25 N.sub.3.2HCl.5/4H.sub.2 O: C, 62.94,
H, 6.77, N, 9.57. Found: C, 62.90, H, 6.93, N, 9.46.
EXAMPLE 27
6-(4-{2-[4-(1-Phenyl-1H-tetrazol-5-yl)-piperazin-1-yl]-ethyl}-phenyl)-pyrid
in-2-ylamine
Prepared as in Example 1, using
4-(N-phenyltetrazol-5-yl)piperazine, in 50% yield, mp
212-214.degree. C.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 2.55 (m, 4H), 2.64 (m, 2H),
2.80 (m, 2H), 3.28 (m, 4H), 4.52 (bs, 2H, NH), 6.42 (d, J=8, 1H),
7.04 (d, J=7, 1H), 7.23 (m, 2H), 7.4-7.6 (m, 6H), 7.81 (m, 2H).
.sup.13 C-NMR (CDCl.sub.3, .delta.): 33.2, 48.7, 52.1, 60.0, 107.0,
110.7, 123.7, 123.8, 126.9, 128.9, 129.7, 129.9, 130.1, 135.0,
137.7, 138.4, 140.5, 155.9, 157.5, 158.2, 160.8. MS (%): 427
(parent+1, 100), 197 (85). Anal. Calc'd. for C.sub.24 H.sub.26
N.sub.8.1/2H.sub.2 O: C, 66.19, H, 6.25, N, 25.73. Found: C, 66.03,
H, 6.24, N, 25.88.
EXAMPLE 28
2-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-1,2,3,4-tetrahydro-isoquinoli
ne-3-carboxylic Acid
Prepared as in Example 1, using
3-carboxy(1,2,3,4-tetrahydroisoquinoline), in 17% yield, mp
110.degree. C. (dec.) as the hydrochloride salt.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 2.9-3.1 (m, 6H), 3.7 (m, 1H),
4.4 (m, 2H), 4.54 (bs, 2H, NH), 6.43 (d, J=8, 1H), 7.0-7.2 (m, 4H),
7.05 (d, J=7, 1H), 7.28 (m, 2H), 7.47 (t, J=8, 1H), 7.86 (m, 2H).
.sup.13 C-NMR (CDCl.sub.3, .delta.): 31.6, 34.8, 47.2, 55.9, 65.3,
107.0, 110.7, 126.1, 126.2, 127.0, 129.1, 133.1, 134.8, 138.1,
138.2, 138.4, 155.8, 158.3, 173.1. MS (%): 374 (parent+1, 81), 197
(100). Anal. Calc'd. for C.sub.23 H.sub.23 N.sub.3
O.sub.2.HCl.1/4H.sub.2 O: C, 60.13, H, 6.47, N, 9.15. Found: C,
60.54, H, 6.07, N, 8.78.
EXAMPLE 29
4-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-piperazine-1-carboxylic
Acid (4-chloro-phenyl)-amide
Prepared as in Example 4, using 4-chlorophenylisocyanate, in 75.5%
yield, mp 160-162.degree. C.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 2.49 (m, 4H), 2.60 (m, 2H),
2.80 (m, 2H), 3.47 (m, 4H), 4.69 (bs, 2H, NH), 6.40 (d, J=8, 1H),
6.96 (d, J=7, 1H), 7.1-7.4 (m, 6H), 7.44 (t, J=8, 1H), 7.73 (m,
2H). .sup.13 C-NMR (CDCl.sub.3, .delta.): 33.0, 43.7, 52.7, 60.0,
107.3, 110.9, 121.4, 121.5, 127.0, 127.9, 128.7, 128.9, 137.7,
137.8, 138.6, 140.4, 155.3, 155.9, 158.4. MS (%): 436 (parent+1,
24), 283 (27), 155 950), 119 (100). Anal. Calc'd. for C.sub.24
H.sub.26 N.sub.5 OCl: C, 66.12, H, 6.01, N, 16.06. Found: C, 65.92,
H, 6.21, N, 16.18.
EXAMPLE 30
4-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-piperazine-1-carboxylic
Acid p-tolyl-amide
Prepared as in Example 4, using 4-methylphenylisocyanate, in 79%
yield, mp 160-162.degree. C.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 2.28 (s, 3H), 2.52 (m, 4H),
2.64 (m, 2H), 2.82 (m, 2H), 3.49 (m, 4H), 4.52 (bs, 2H, NH), 6.42
(d, J=8, 1H), 6.44 (m, 1H), 7.0-7.1 and 7.2-7.4 (m, 6H), 7.47 (d,
J=8, 1H), 7.84 (m, 2H). .sup.13 C-NMR (CDCl.sub.3, .delta.): 20.8,
33.25, 44.1, 52.8, 60.1, 107.0, 110.7, 120.3, 126.9, 128.9, 129.4,
136.4, 137.7, 138.4, 140.6, 155.2, 155.9, 158.2. MS (%): 416
(parent+1, 71), 283 (100), 2332 (73), 197 (70), 119 (53), 99 (66).
Anal. Calc'd. for C.sub.25 H.sub.29 N.sub.5 O: C, 72.26, H, 7.03,
N, 16.85. Found: C, 72.07, H, 7.13, N, 16.99.
EXAMPLE 31
4-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-piperazine-1-carboxylic
Acid (4-methoxy-phenyl)-amide
Prepared as in Example 4, using 4-methoxyphenylisocyanate, in 80%
yield, mp 182-184.degree. C.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 2.53 (m, 4H), 2.66 (m, 2H),
2.83 (m, 2H), 3.49 (m, 4H), 3.75 (s, 3H), 4.57 (bs, 2H, NH), 6.42
(d, J=8, 1H), 6.80 (m, 2H), 7.02 (d, J=7, 1H), 7.1-7.3 (m, 4H),
7.47 (t, J=8, 1H), 7.80 (m, 2H). .sup.13 C-NMR (CDCl.sub.3,
.delta.): 33.1, 44.0, 52.7, 52.8, 60.1, 107.1, 110.8, 114.1, 122.4,
122.6, 126.9, 128.9, 131.9, 137.7, 138.5, 140.5, 155.7, 155.9,
158.3. MS (%): 432 (parent+1, 15.5), 283 (20), 155 (50), 119 (100),
103 (47). Anal. Calc'd. for C.sub.25 H.sub.29 N.sub.5
O.sub.2.1/4H.sub.2 O: C, 68.86, H, 6.82, N, 16.06. Found: C, 68.80,
H, 6.80, N, 16.20.
EXAMPLE 32
4-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-piperazine-1-carboxylic
Acid Cyclohexylamide
Prepared as in Example 4, using cyclohexylisocyanate, in 79% yield,
mp 180-182.degree. C.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 1.1 (m, 3H), 1.3 (m, 2H), 1.8
(m, 3H), 2.0 (m, 2H), 2.48 (m, 4H), 2.63 (m, 2H), 2.82 (m, 2H),
3.36 (m, 4H), 3.63 (m, 1H), 4.30 (d, J=5, 1H, NH), 4.54 (bs, 2H,
NH), 6.41 (d, J=8, 1H), 7.03 (d, J=8, 1H), 7.25 (m, 2H), 7.46 (t,
J=8, 1H), 7.82 (m, 2H). .sup.13 C-NMR (CDCl.sub.3, .delta.): 25.1,
25.7, 33.3, 34.0, 43.7, 49.4, 52.8, 60.2, 106.9, 110.7, 126.9,
137.6, 138.4, 140.6, 155.9, 157.0, 158.2. MS (%): 408 (parent+1,
55), 283 (100), 224 (50), 197 (60), 119 (44). Anal. Calc'd. for
C.sub.24 H.sub.33 N.sub.5 O.1/4H.sub.2 O: C, 69.96, H, 8.19, N,
17.00. Found: C, 70.13, H, 8.32, N, 17.19.
EXAMPLE 33
4-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-piperazine-1-carboxylic
Acid phenyl Ester
Prepared as in Example 4, using phenyl chloroformate, in 19% yield,
mp 102-104.degree. C.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 2.57 (m, 4H), 2.69 (m, 2H),
2.83 (m, 2H), 3.6-3.8 (m, 4H), 4.52 (bs, 2H, NH), 6.42 (d, J=8,
1H), 7.1-7.4 (m, 7H), 7.48 (t, J=8, 1H), 7.85 (m, 2H). .sup.13
C-NMR (CDCl.sub.3, .delta.): 33.3, 44.0, 44.5, 52.5, 53.0, 60.2,
107.0, 110.7, 121.7, 125.3, 127.0, 128.9, 129.3, 137.7, 138.4,
140.6, 151.4, 153.7, 155.95, 158.2. MS (%): 403 (parent+1, 100),
219 (90), 197 (77). Anal. Calc'd. for C.sub.24 H.sub.26 N.sub.4
O.sub.2 : C, 71.62, H, 6.51, N, 13.92. Found: C, 71.23, H, 6.55, N,
14.01.
EXAMPLE 34
6-(4-{2-[4-(1-Phenyl-1H-imidazol-2-yl)-piperazin-1-yl]-ethyl}-phenyl)-pyrid
in-2-ylamine
Prepared as in Example 1, using (N-phenylimidazol-2-yl)piperazine,
in 63% yield, mp 140-142.degree. C.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 2.49 (m, 4H), 2.60 (m, 2H),
2.76 (m, 2H), 3.07 (m, 4H), 4.55 (bs, 2H, NH), 6.39 (d, J=8, 1H),
6.84 (s, 2H), 7.01 (d, J=7, 1H), 7.22 (m, 2H), 7.3-7.6 (m, 6H),
7.80 (m, 2H). .sup.13 C-NMR (CDCl.sub.3, .delta.): 33.3, 49.6,
52.7, 60.6, 106.9, 110.6, 118.3, 123.8, 125.4, 126.8, 127.2, 128.9,
129.4, 137.6, 138.3, 140.75, 151.3, 156.0, 158.3. MS (%): 425
(parent+1, 100), 241 (33), 197 (40), 184 (32), 172 (55), 160 (38).
Anal. Calc'd. for C.sub.26 H.sub.28 N.sub.6.1/4H.sub.2 O: C, 72.79,
H, 6.70, N, 19.59. Found: C, 72.63, H, 6.56, N, 19.66.
EXAMPLE 35
6-[4-(2-Phenethylamino-ethyl)-phenyl]-pyridin-2-ylamine
Prepared as in Example 1, using benzylamine, in 38% yield, mp
212-215.degree. C. as the hydrochloride salt.
.sup.1 H-NMR (CD.sub.3 OD, .delta.) hydrochloride salt: 3.04 (m,
2H), 3.14 (m, 2H), 3.30 (m, 4H), 6.99 (d, J=8, 1H), 7.17 (d, J=7,
1H), 7.2-7.4 (m, 5H), 7.55 (m, 2H), 7.83 (m, 2H), 7.97 (m, 1H).
.sup.13 C-NMR (CDCl.sub.3, .delta.): 33.0, 33.4, 111.9, 112.9,
128.3, 128.9, 129.8, 130.0, 131.1, 132.0, 137.8, 141.7, 145.9,
147.9, 156.8. MS (%): 318.3009 (parent+1, 100, calculated
318.19702). Anal. Calc'd. for C.sub.21 H.sub.23
N.sub.3.2HCl.H.sub.2 O: C, 61.77, H, 6.66, N, 10.29. Found: C,
61.49, H, 6.67, N, 10.35.
EXAMPLE 36
1-(3-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-3-aza-bicyclo[3.1.
0]hex-6-yl)-3-phenyl-urea
Prepared from the final compound in Example 2, using
phenylisocyanate, in 67% yield, mp 192-194.degree. C.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 1.59 (m, 2H), 2.52 (m, 2H),
2.65 (m, 2H), 2.78 (m, 2H), 3.30 (m, 2H), 3.34 (m, 1H), 6.50 (d,
J=8, 1H), 6.97 (m, 2H), 7.2-7.4 (m, 6H), 7.48 (t, J=8, 1H), 7.74
(m, 2H). .sup.13 C-NMR (CDCl.sub.3, .delta.): 25.8, 31.8, 35.9,
55.9, 58.5, 108.5, 111.2, 120.4, 123.6, 128.0, 129.8, 129.9, 139,1,
139.7, 140.7, 142.1, 157.2, 158.9, 160.9. MS (%): 414 (parent+1,
100), 226 (40), 149 (81), 127 (63). Anal. Calc'd. for C.sub.25
H.sub.27 N.sub.5 O: C, 72.61, H, 6.58, N, 16.94. Found: C, 72.34,
H, 6.24, N, 17.00.
EXAMPLE 37
(3-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-3-aza-bicyclo[3.1.
0]hex-6-yl)-dimethyl-amine
Prepared from the final compound in Example 2, using formaldehyde
in formic acid at 80.degree. C. for 2.5 hr, in 56.5% yield, as an
amorphous solid.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 1.47 (m, 2H), 1.89 (m, 1H),
2.31 (s, 6H), 2.41 (m, 2H), 2.66 (m, 2H), 2.74 (m, 2H), 3.08 (m,
2H), 4.52 (bs, 2H, NH), 6.42 (d, J=8, 1H), 7.05 (d, J=7, 2H), 7.24
(m, 2H), 7.47 (t, J=8, 1H), 7.83 (m, 2H). .sup.13 C-NMR
(CDCl.sub.3, .delta.): 24.8, 35.3, 45.1, 48.3, 55.0, 57.4, 106.8,
110.7, 459.7, 128.8, 137.5, 138.3, 141.1, 156.1, 158.2. MS (%): 323
(parent+1, 7), 167 (35), 149 (100), 113 (37). Anal. Calc'd. for
C.sub.20 H.sub.26 N.sub.4. 3HCl.H.sub.2 O: C, 53.40, H, 6.45, N,
12.45. Found: C, 53.44, H, 7.03, N, 12.32.
EXAMPLE 38
N-(3-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-3-aza-bicyclo[3.1.
0]hex-6-yl)-2-(4-fluoro-phenyl)-acetamide
Prepared from the final compound in Example 2, using
4-fluorophenylacetic acid coupling mediated by N-ethyl,
N-(3-dimethylaminopropyl)carbodiimide, in 38% yield, mp
161-163.degree. C.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 1.42 (m, 2H), 2.36 (m, 2H),
2.63 (m, 2H), 2.70 (m, 2H), 2.88 (m, 1H), 3.15 (m, 2H), 3.45 (s,
2H), 4.51 (bs, 2H, NH), 5.49 (bs, 1H, NH), 6.42 (d, J=8, 1H),
7.0-7.3 (m, 7H), 7.46 (t, J=8, 1H), 7.80 (m, 2H). .sup.13 C-NMR
(CDCl.sub.3, .delta.): 24.3, 30.5, 35.1, 42.8, 54.4, 56.7, 106.9,
110.7, 115.6, 115.9, 126.7, 128.8, 130.8, 130.9, 137.4, 138.3,
141.0, 156.0, 158.2, 160.4, 163.7, 171.5. MS (%): 431 (parent+1,
100), 226 (33), 197 (60), 109 (60). Anal. Calc'd. for C.sub.26
H.sub.27 FN.sub.4 O.1/2H.sub.2 O: C, 71.05, H, 6.42, N, 12.75.
Found: C, 71.14, H, 6.53, N, 12.60.
EXAMPLE 39
6-(4-{2-[4-(3-Phenyl-allyl)-piperazin-1-yl]-ethyl}-phenyl)-pyridin-2-ylamin
e
Prepared as in Example 1, using (3-phenyl-allyl)-piperazine, in 67%
yield, mp 249-255.degree. C. (hydrochloride salt).
.sup.1 H-NMR as the hydrochloride salt (CDCl.sub.3 /MeOD, .delta.):
3.27 (m, 2H), 3.56 (m, 2H), 3.7-4.0 (m, 8H), 4.08 (d, J=7, 2H),
6.34 (m, 2H), 6.95 (m, 2H), 7.11 (d, J=7, 1H), 7.33 (m, 2H), 7.51
(m, 3H), 7.79 (m, 2H), 7.93 (dd, J=7,8, 1H). .sup.13 C-NMR
(CDCl.sub.3, .delta.): 27.1, 31.1, 57.0, 58.1, 59.9, 112.0, 113.2,
116.5, 128.4, 1218.5, 128.8, 129.0, 131.9, 136.4, 141.0, 143.2,
145.8, 147.8, 150.3, 156.8. MS (%): 399 (parent+1, 54), 149 (77),
119 (93), 117 (100). Anal. Calc'd. for C.sub.26 H.sub.30
N.sub.4.3HCl.1/2H.sub.2 O: C, 60.41, H, 6.63, N, 10.84. Found: C,
60.79, H, 6.65, N, 10.67.
EXAMPLE 40
6-(4-{2-[4-(3-Phenyl-propyl)-piperazin-1-yl]-ethyl}-phenyl)-pyridin-2-ylami
ne
Prepared as in Example 1, using (3-phenyl-propyl)-piperazine, in
64% yield, mp 258-264.degree. C. (hydrochloride salt).
.sup.1 H-NMR (CDCl.sub.3, .delta.): 1.83 (qn, J=8, 2H), 2.54 (m,
2H), 2.6-2.8 (m, 12H), 2.83 (m, 2H), 4.47 (bs, 2H, NH), 6.42 (d,
J=8, 1H), 7.05 (d, J=7, 1H), 7.1-7.3 (m, 7H), 7.46 (t, J=8, 1H),
7.82 (m, 2H). .sup.13 C-NMR (CDCl.sub.3, .delta.): 28.6, 33.3,
33.7, 53.2, 58,0, 60.3, 65.8, 106.8, 110.7, 125.8, 126.8, 128.3,
128.4, 128.9, 137.6, 138.3, 140.9, 142.1, 156.1, 158.2. MS (%): 401
(parent+1, 10), 167 (21), 149 (100), 113 (24). Anal. Calc'd. for
C.sub.26 H.sub.32 N.sub.4.3HCl.5/2H.sub.2 O: C, 56.27, H, 7.26, N,
10.10. Found: C, 56.35, H, 7.47, N, 9.72.
EXAMPLE 41
4-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-piperazine-1-carboxylic
Acid (3,4-dimethyl-phenyl)-amide
Prepared as in Example 4, using 3,4-dimethylphenylisocyanate, in
90% yield, mp 122-125.degree. C.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 2.15 (s, 3H), 2.18 (s, 3H),
2.47 (m, 4H), 2.65 (m, 2H), 2.85 (m, 2H), 3.55 (m, 4H), 4.55 (bs,
2H, NH), 6.35 (s, 1H), 6.42 (d, J=8, 1H), 7.0-7.3 (m, 5H), 7.47 (t,
J=8, 1H), 7.82 (m, 2H). .sup.13 C-NMR (CDCl.sub.3, .delta.): 19.0,
19.9, 33.2, 44.1, 52.8, 60.1, 104.0, 110.7, 117.7, 121.7, 126.9,
128.9, 129., 131.4, 136.6, 137.0, 137.6, 138.4, 140.6, 155.2,
155.9, 158.2. MS (%): 430 (parent+1, 41), 283 (100), 246 (58), 197
(81), 99 (76). Anal. Calc'd. for C.sub.26 H.sub.31 N.sub.5 O: C,
72.70, H, 7.27, N, 16.30. Found: C, 72.51, H, 7.33, N, 16.06.
EXAMPLE 42
1-(4-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-piperazin-1-yl)-2-(4-chlor
o-phenyl)-ethanone
Prepared as in Example 5, using 4-chlorophenylacetic acid, in 38%
yield, mp 205.degree. C. (dec., hydrochloride salt).
.sup.1 H-NMR (CDCl.sub.3, .delta.): 2.37 (m, 2H), 2.49 (m, 2H),
2.59 (m, 2H), 2.62 (m, 2H), 3.45 (m, 2H), 3.6 (m, 2H), 3.67 (s,
2H), 4.86 (bs, 2H, NH), 6.42 (d, J=8, 1H) 7.01 (d, J=7, 1H),
7.1-7.3 (m, 6H), 7.47 (dd, J=7,8, 1H), 7.79 (m, 2H). .sup.13 C-NMR
(CDCl.sub.3, .delta.): 33.1, 40.0, 41.7, 45.9, 52.6, 53.0, 59.8,
107.2, 110.7, 127.0, 128.5, 128.8, 130.0, 130.8, 122.7, 133.5,
137.3, 138.6, 140.5, 155.6, 158,2, 169.0. MS (%): 435 (parent+1,
100), 251 (49), 197 (61), 119 (62). Anal. Calc'd. for C.sub.25
H.sub.27 N.sub.4 ClO.1/4H.sub.2 O: C, 68.33, H, 6.31, N, 12.75.
Found: C, 68.59, H, 6.13, N, 12.53.
EXAMPLE 43
8-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-3-benzyl-1,3,8-triaza-spiro[4
.5]decane-2,4-dione
Prepared as in Example 1, using
3-benzyl-1,3,8-triaza-spiro[4.5]decane-2,4-dione (prepared as
described in WO 95/12577 (1995)), in 42% yield, mp 190.degree. C.
(dec., as the hydrochloride salt).
.sup.1 H-NMR (CDCl.sub.3, .delta.): 1.62 (m, 2H), 2.11 (m, 2H),
2.23 (m, 2H), 2.63 (m, 2H), 2.82 (m, 2H), 2.95 (m, 2H), 4.50 (bs,
2H, NH), 4.63 (s, 2H), 6.41 (d, J=8, 1H), 7.04 (d, J=7, 1H),
7.2-7.4 (m, 7H), 7.46 (dd, J=7,8, 1H), 7.83 (m, 2H). .sup.13 C-NMR
(CDCl.sub.3, .delta.): 33.2, 33.4, 42.1, 49.0, 60.1, 60.2, 106.9,
110.7, 126.9, 127.8, 128.3, 128.7, 128.9, 136.1, 167.7, 138.4,
140.7, 155.9, 156.8, 158.2, 176.0. MS (%): 456 (parent+1, 100), 272
(81), 197 (79), 119 (35). Anal. Calc'd. for C.sub.27 H.sub.29
N.sub.5 O.sub.2.1/2H.sub.2 O (analyzed as the free base): C, 69.81,
H, 6.51, N, 15.07. Found: C, 69.94, H, 6.52, N, 15.00.
EXAMPLE 44
3-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-3-aza-bicyclo[3.2.
1]oct-8-ylamine
Prepared as in Example 2, using 3-aza-bicyclo[3.2.1]oct-8-ylamine
t-butylcarbamate followed by removral of the t-butylcarbamate
group, in 83% yield, mp 235.degree. C. (dec., as the hydrochlorides
salt).
.sup.1 H-NMR (CDCl.sub.3, .delta.): 1.69 (m, 4H), 1.82 (m, 2H),
2.59 (m, 6H), 2.75 (m, 2H), 2.97 (m, 1H), 4.53 (bs, 2H, NH), 6.39
(d, J=8, 1H), 7.03 (d, J=7, 1H), 7.24 (m, 2H), 7.43 (dd, J=7,8,
1H), 7.82 (m, 2H). .sup.13 C-NMR (CDCl.sub.3, .delta.): 26.9, 33.2,
39.2, 52.1, 54.1, 59.7, 106.8, 110.65, 126.6, 128.9, 139.3, 138.3,
141.6, 156.1, 158.2. MS (%): 323 (parent+1, 10), 167 (24), 149
(100), 113 (27). Anal. Calc'd. for C.sub.20 H.sub.26
N.sub.4.HCl.7/4H.sub.2 O.CH.sub.2 Cl.sub.2 : C, 53.06, H, 6.89, N,
11.79. Found: C, 53.35, H, 7.07, N, 11.79.
EXAMPLE 45
4-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-piperazine-1-carboxylic
Acid m-tolyl-amide
Prepared as in Example 3, using 3-tolylisocyanate, in 85% yield, mp
88-94.degree. C.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 2.30 (s, 3H), 2.52 (m, 4H),
2.64 (m, 2H), 2.83 (m, 2H), 3.50 (m, 4H), 4.54 (bs, 2H, NH), 6.42
(d, J=8, 1H), 6.48 (s, 1H), 6.83 (d, J=7, 1H), 7.04 (d, J=7, 1H),
7.1-7.3 (m, 4H), 7.47 (t, J=8, 1H), 7.83 (m, 2H). .sup.13 C-NMR
(CDCl.sub.3, .delta.): 21.5, 33.2, 44.1, 52.8, 60.1, 107.0, 110.7,
117.1, 120.8, 123.9, 126.9, 128.7, 128.9, 137.7, 138.4, 138.7,
138.9, 140.6, 155.1, 155.9, 158.2. MS (%): 416 (parent+1, 33), 283
(100), 232 (60), 197 (95). Anal. Calc'd. for C.sub.25 H.sub.29
N.sub.5 O: C, 72.26, H, 7.03, N, 16.85. Found: C, 72.08, H, 7.08,
N, 16.74.
EXAMPLE 46
(3-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-3-aza-bicyclo[3.1.
0]hex-6-yl)-phenethyl-amine
Prepared using the final product of Example 2, by reaction with
phenylacetaldehyde and sodium cyanoborohydride in methanol, in 41%
yield, mp 165.degree. C. (dec., as the hydrochloride salt. .sup.1
H-NMR (CDCl.sub.3, .delta.): 1.43 (m, 2H), 2.4 (m, 3H), 2.6 (m,
2H), 2.8 (m, 4H), 2.92 (m, 2H), 3.09 (m, 2H), 4.51 (bs, 2H, NH),
6.41 (d, J=8, 1H), 7.04 (d, J=7, 1H), 7.1-7.3 (m, 7H), 7.43 (t,
J=8, 1H), 7.82 (m, 2H). .sup.13 C-NMR (CDCl.sub.3, .delta.): 24.4,
35.0, 36.1, 39.0, 50.6, 55.0, 57.3, 106.9, 110.7, 126.1, 126.8,
128.5, 128.7, 128.9, 137.6, 138.35, 140.0, 140.7, 156.0, 158.2.
HRMS (%): Calc'd. for C.sub.26 H.sub.30 N.sub.4 : 399.2549. Found:
399.2534.
EXAMPLE 47
4-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-piperazine-1-carboxylic
Acid Benzylamide
Prepared as in Example 3, using benzylisocyanate, in 60% yield, mp
172-175.degree. C.
.sup.1 H-NMR (MeOD, CDCl.sub.3, .delta.): 2.48 (m, 4H), 2.63 (m,
2H), 2.80 (m, 2H), 3.39 (m, 4H), 4.37 (s, 2H), 4.61 (bs for
NH.sub.2, partly exchanged), 5.03 (m, NH, partly exchanged), 6.41
(d, J=8, 1H), 6.99 (d, J=7, 1H), 7.1-7.3 (m, 7H), 7.45 (t, J=8,
1H), 7.76 (m, 2H). .sup.13 C-NMR (CDCl.sub.3, .delta.): 33.1, 43.6,
44.8, 52.8, 60.1, 107.1, 110.8, 126.9, 127.3, 127.7, 128.6, 128.9,
137.7, 138.5, 139.3, 140.5, 155.9, 157.7, 158.3. MS (%): 416
(parent+1, 10), 283 (100), 232 (56), 197 (80), 99 (70). Anal.
Calc'd. for C.sub.25 H.sub.29 N.sub.5 O.1/4H.sub.2 O: C, 71.49, H,
7.28, N, 16.67. Found: C, 71.45, H, 7.06, N, 16.67.
EXAMPLE 48
6-[4-(2-{4-[1-(4-Fluoro-phenyl)-1H-tetrazol-5-yl]-piperazin-1-yl}-ethyl)-ph
enyl]-pyridin-2-ylamine
Prepared as in Example 1, using
[(4-fluoro-phenyl)-1H-tetrazol-5-yl]piperazine, in 20% yield, mp
185-187.degree. C.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 2.58 (m, 4H), 2.67 (m, 2H),
2.81 (m, 2H), 3.28 (m, 4H), 4.51 (bs, 2H, NH), 6.45 (d, J=8,1H),
7.06 (d, J=7, 1H), 7.2-7.3 (m, 4H), 7.49 (t, J=8, 1H), 7.60 (m,
2H), 7.85 (m, 2H). .sup.13 C-NMR (CDCl.sub.3, .delta.): 33.2, 48.7,
52.1, 60.0, 106.9, 110.7, 116.8, 117.1, 125.8, 125.9, 126.9, 128.9,
131.0, 137.7, 138.4, 140.4, 155.9, 157.6, 158.2, 161.1, 164.5. MS
(%): 445 (parent+1, 85), 197 (80), 119 (100), 103 (84). Anal.
Calc'd. for C.sub.24 H.sub.25 N.sub.8 F: C, 64.85, H, 5.67, N,
25.21. Found: C, 64.63, H, 5.75, N, 25.36.
EXAMPLE 49
6-(4-{2-[4-cis-(4-Phenyl-cyclohexyl)-piperazin-1-yl]-ethyl}-phenyl)-pyridin
-2-ylamine
Prepared as in Example 1, using
cis-(4-phenyl-cyclohexyl)-piperazine, in 46% yield, mp
127-130.degree. C.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 1.58 (m, 4H), 1.95 (m, 4H),
2.27 (m, 1H), 2.6-2.8 (m, 10H), 2.83 (m, 2H), 4.50 (bs, 2H, NH),
6.42 (d, J=8, 1H), 7.06 (d, J=7, 1H), 7.2-7.3 (m, 7H), 7.47 (t,
J=8, 1H), 7.85 (m, 2H). .sup.13 C-NMR (CDCl.sub.3, .delta.): 28.0,
28.4, 33.4, 42.8, 49.8, 53.8, 59.1, 60.5, 106.9, 110.7, 125.7,
126.8, 127.1, 128.2, 128.9, 129.2, 137.6, 138.3, 141.0, 147.1,
156.1, 158.2. MS (%): 441 (parent+1, 59), 257 (75), 197 (40), 91
(100). Anal. Calc'd. for C.sub.29 H.sub.36 N.sub.4 O.1/4H.sub.2 O:
C, 78.25, H, 8.27, N, 12.59. Found: C, 78.30, H, 8.22, N,
12.70.
EXAMPLE 50
6-(4-{2-[4-trans-(4-Phenyl-cyclohexyl)-piperazin-1-yl]-ethyl}-phenyl)-pyrid
in-2-ylamine
Prepared as in Example 1, using
trans-(4-phenyl-cyclohexyl)-piperazine, in 54% yield, mp
178-180.degree. C.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 1.49 (m, 4H), 2.03 (m, 4H),
2.47 (m, 2H), 2.65 (m, 8H), 2.85 (m, 2H), 4.50 (bs, 2H, NH), 6.42
(d, J=8, 1H), 7.05 (d, J=7, 1H), 7.1-7.2 (m, 7H), 7.47 (t, J=8,
1H), 7.84 (m, 2H). .sup.13 C-NMR (CDCl.sub.3, .delta.): 28.9, 33.3,
33.5, 44.1, 49.1, 53.5, 60.4, 63.3, 106.9, 110.7, 126.0, 126.8,
126.9, 128.3, 128.9, 137.6, 138.3, 140.9, 146.9, 156.0, 158.2. MS
(%): 441 (parent+1, 39), 257 (90), 197 (40), 91 (100). Anal.
Calc'd. for C.sub.29 H.sub.36 N.sub.4 O.1/4H.sub.2 O: C, 78.25, H,
8.27, N, 12.59. Found: C, 77.98, H, 8.25, N, 12.60.
EXAMPLE 51
(3-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-3-aza-bicyclo[3.1.
0]hex-6-yl)-(3-phenyl-propyl)-amine Hydrochloride Salt
Prepared from the final compound in Example 2, using
3-phenylpropionaldehyde via reductive amination using sodium
cyanoborohydride in methanol, in 27% yield, mp 160-163.degree. C.
as the hydrochloride salt from 1,2-dichloroethane.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 1.44 (m, 2H), 1.83 (qn, 2H),
2.43 (m, 3H), 2.6-2.8 (m, 8H), 3.09 (m, 2H), 4.54 (bs, 2H, NH),
6.43 (d, J=8, 1H), 7.07 (d, J=7, 1H), 7.1-7.3 (m, 7H), 7.48 (t,
J=8, 1H), 7.85 (m, 2H). .sup.13 C-NMR (CDCl.sub.3, .delta.): 24.4,
31.5, 33.6, 35.2, 39.0, 49.1, 55.0, 57.3, 106.8, 110.7, 125.8,
126.7, 128.3, 128.4, 128.9, 137.5, 138.3, 141.0, 142.1, 156.1,
158.2. MS (%): 413 (parent+1, 70), 226 (73), 197 (66), 91 (100).
Anal. Calc'd. for C.sub.27 H.sub.32 N.sub.4.2HCl.2H.sub.2
O.1/2C.sub.2 H.sub.4 Cl.sub.2 : C, 58.90, H, 7.06, N, 9.81. Found:
C, 59.19, H, 7.18, N, 9.46.
EXAMPLE 52
2-(3-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-3-aza-bicyclo[3.1.
0]hex-6-ylamino)-acetamide
Prepared trom the final compound in Example 2, using iodoacetamide,
in 39.5% yield, mp 140.degree. C. (dec.).
.sup.1 H-NMR (CDCl.sub.3, .delta.): 1.51 (m, 2H), 2.41 (m, 1H),
2.50 (m, 2H), 2.65 (m, 2H), 2.75 (m, 2H), 3.05 (m, 2H), 3.25 (s,
2H), 6.49 (d, J=8, 1H), 6.96 (d, J=7, 1H), 7.24 (m, 2H), 7.48 (dd,
J=7,8, 1H), 7.74 (m, 2H). .sup.13 C-NMR (CDCl.sub.3, .delta.):
25.3, 35.7, 40.6, 56.1, 58.6, 60.1, 108.5, 111.1, 128.0, 129.8,
139.2, 139.7, 141.9, 157.1, 161.0, 177.0. HRMS (%): 352 (parent+1,
43), 155 (47), 119 (100), 103 (54).
EXAMPLE 53
6-[4-(2-{4-[2-(4-Fluoro-phenyl)-ethyl]-piperazin-1-yl}-ethyl)-phenyl]-pyrid
in-2-ylamine
Prepared as in Example 1, using (4-fluoro)phenethyl-piperazine, in
35% yield, mp 165-167.degree. C.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 2.5-2.7 (m, 12H), 2.7-2.9 (m,
4H), 4.51 (bs, 2H, NH), 6.42 (d, J=8, 1H), 6.95 (m, 2H), 7.05 (d,
J=8, 1H), 7.14 (m, 2H), 7.25 (m, 2H), 7.47 (t, J=8, 1H), 7.83 (m,
2H). .sup.13 C-NMR (CDCl.sub.3, .delta.): 32.8, 33.3, 53.1, 60.3,
60.5, 106.9, 110.7, 115.0, 115.3, 126.8, 128.9, 130.0, 130.1,
135.9, 136.0, 137.6, 138.3, 140.9, 156.1, 158,2, 159.8, 163.0. MS
(%): 405 (parent+1, 92), 221 (100), 197 (53), 123 (75). Anal.
Calc'd. for C.sub.25 H.sub.29 FN.sub.4.1/4H.sub.2 O: C, 72.61, H,
7.31, N, 13.55. Found: C, 72.74, H, 7.05, N, 13.22.
EXAMPLE 54
6-(4-{2-[4-(1-Methyl-2-phenyl-ethyl)-piperazin-1-yl]-ethyl}-phenyl)-pyridin
-2-ylamine
Prepared as in Example 1, using 1-methyl-2-phenyl-ethyl-piperazine,
in 30% yield, mp 252-256.degree. C. as the hydrochloride salt.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 0.95 (d, J=6, 3H), 2.41 (m,
1H), 2.5-2.7 (m, 10H), 2.83 (m, 3H), 3.04 (m, 1H), 4.54 (bs, 2H,
NH), 6.41 (d, J=8, 1H), 7.04 (d, J=7, 1H), 7.1-7.3 (m, 7H), 7.46
(t, J=8, 1), 7.84 (m, 2H). .sup.13 C-NMR (CDCl.sub.3, .delta.):
14.4, 33.4, 39.3, 48.3, 53.6, 60.4, 61.3, 106.9, 110.7, 125.8,
126.9, 127.0, 128.2, 128.9, 129.3, 137.6, 138.3, 140.6, 140.9,
156.1, 158.3. MS (%): 401 (parent+1, 64), 309 (35), 217 (40), 197
(34), 91 (100). Anal. Calc'd. for C.sub.28 H.sub.32
N.sub.4.3HCl.H.sub.2 O: C, 59.15, H, 7.06, N, 10.61. Found: C,
59.07, H, 7.22, N, 10.46.
EXAMPLE 55
6-(4-{2-[4-(1,2,3,4-Tetrahydro-naphthalen-2-yl)-piperazin-1-yl]-ethyl}-phen
yl)-pyridin-2-ylamine
Prepared as in Example 1 using
4-(1,2,3,4-tetrahydro-naphthalen-2-yl)-piperazine, in 33% yield,
mp>220.degree. C. as the hydrochloride salt.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 1.65 (m, 1H), 2.15 (m, 1H),
2.6-3.0 (m, 17H), 4.52 (bs, 2H, NH), 6.41 (d, J=8, 1H), 7.09 (m,
5H), 7.26 (m, 2H), 7.46 (t, J=8, 1H), 7.84 (m, 2H). .sup.13 C-NMR
(CDCl.sub.3, .delta.): 26.1, 29.4, 32.0, 33.3, 49.1, 53.5, 60.3,
60.4, 106.9, 110.7, 125.7, 125.8, 126.9, 128.5, 128.9, 129.5,
135.9, 136.4, 137.6, 138.3, 140.9, 156.1, 158.2. MS (%): 413
(parent+1, 30), 229 (65), 197 (30), 131 (100). Anal. Calc'd. for
C.sub.27 H.sub.32 N.sub.4.3HCl: C, 62.13, H, 6.76, N, 10.73. Found:
C, 62.44, H, 7.11, N, 10.49.
EXAMPLE 56
N-(1-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-pyrrolidin-3-yl)-2-(4-fluo
ro-phenyl)-acetamide
Prepared from
(1-{2-[4-(6-amino-pyridin-2-yl)-phenyl]-ethyl}-pyrrolidin-3-yl)-2-amine,
using 4-fluorophenylacetic acid coupling mediated by N-ethyl,
N-(3-dimethylaminopropyl)carbodiimide, in 55% yield, mp 90.degree.
C. (dec.).
.sup.1 H-NMR (CDCl.sub.3, .delta.): 1.54 (m, 2H), 2.24 (m, 3H),
2.53 (m, 1H), 2.72 (m, 2H), 2.79 (m, 2H), 2.98 (m, 1H), 4.5 (m,
2H), 6.19 (m, 1H), 6.40 (d, J=8, 1H), 7.02 (m, 3H), 7.20 (m, 4H),
7.46 (t, J=8, 1H), 7.82 (m, 2H). .sup.13 C-NMR (CDCl.sub.3,
.delta.): 32.1, 34.6, 42.7, 48.6, 52.8, 57.2, 60.6, 107.0, 110.7,
115.5, 115.7, 126.9, 128.8, 131.8, 130.9, 137.8, 138.4, 140.2,
155.8, 158.3, 160.8, 163.2, 170.2. MS (%): 419 (parent+1, 43), 391
(38), 167 (40), 149 (100), 119 (46), 113 (73). HRMS: Calc'd. for
C.sub.25 H.sub.28 N.sub.4 OF: 419.2247. Found: 419.2266.
EXAMPLE 57
8-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-3-phenethyl-1,3,8-triaza-spir
o[4.5]decane-2,4-dione
Prepared as in Example 1, using
3-phenethyl-1,3,8-triaza-spiro[4.5]decane-2,4-dione, in 45% yield,
mp 176-180.degree. C. as the hydrochloride salt.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 1.51 (m, 2H), 2.02 (m, 2H),
2.23 (m, 2H), 2.63 (m, 2H), 2.82 (m, 2H), 2.92 (m, 4H), 3.73 (t,
J=7, 2H), 4.54 (bs, 2H, NH), 6.42 (d, J=8, 1H), 7.05 (m, 2H),
7.2-7.3 (m, 5H), 7.47 (t, J=8, 1H), 7.83 (m, 2H). .sup.13 C-NMR
(CDCl.sub.3, .delta.): 33.2, 33.3, 33.8, 39.5, 49.0, 59.7, 60.1,
106.9, 110.7, 126.6, 126.9, 128.5, 128.9, 129.0, 137.7, 138.4,
140.7, 156.0, 156.8, 158.3, 176.1. MS (%): 470 (parent+1, 70), 360
(67), 340 (100), 338 (75), 332 (55). Anal. Calc'd. for C.sub.28
H.sub.31 N.sub.5 O.sub.2.1/2H.sub.2 O: C, 70.27, H, 6.74, N, 14.63.
Found: C, 70.16, H, 6.65, N, 14.85.
EXAMPLE 58
8-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-8-aza-bicyclo[3.2.
1]oct-3-ylamine
Prepared as in Example 1, using 8-aza-bicyclo[3.2.1]oct-3-ylamine
as the t-butyl carbamate, followed by deprotection using
trifluoroacetic acid, in 67% yield, mp>300.degree. C. as the
hydrochloride salt.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 1.45 (m, 4H), 1.54 (m, 2H),
1.68 (m, 2H), 1.91 (m, 2H), 2.63 (m, 2H), 2.78 (m, 2H), 2.93 (m,
1H), 3.29 (m, 2H), 4.50 (bs, 2H, NH), 6.39 (d, J=8, 1H), 7.03 (d,
J=7, 1H), 7.24 (m, 2H), 7.45 (t, J=8, 1H), 7.81 (m, 2H). .sup.13
C-NMR (CDCl.sub.3, .delta.): 26.9, 35.6, 41.2, 43.0, 53.3, 58.8,
106.8, 110.7, 126.7, 128.9, 137.5, 138.3, 141.1, 156.0, 158.2. MS
(%): 323 (parent+1, 23), 197 (25), 149 (36), 109 (57), 95 (100).
Anal. Calc'd. for C.sub.20 H.sub.26 N.sub.4.HCl.3/2H.sub.2
O.CH.sub.2 Cl.sub.2 : C, 53.57, H, 6.85, N, 11.90. Found: C, 53.90,
H, 7.09, N, 12.14.
EXAMPLE 59
4-Amino-1{-2-[4-(6-amino-pyridin-2-yl)-phenyl]-ethyl}-piperidine-4-carboxyl
ic Acid benzylamide
Prepared as in Example 1, using 4-amino-piperidine-4-carboxylic
acid benzylamide, mp>240.degree. C. (dec.) as the hydrochloride
salt.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 1.47 (m, 2H), 2.36 (m, 4H),
2.64 (m, 2H), 2.87 (m, 2H), 2.92 (m, 2H), 4.42 (d, J=6, 2H), 4.47
(s, 2H), 6.42 (d, J=8, 1H), 7.05 (d, J=7, 1H), 7.2-7.4 (m, 7H),
7.47 (t, J=8, 1H), 7.83 (m, 2H), 8.02 (bs, 1H, NH). .sup.13 C-NMR
(CDCl.sub.3, .delta.): 33.11, 34.8, 43.2, 48.9, 55.1, 60.3, 107.1,
110.9, 126.9, 127.3, 127.6, 128.6, 128.9, 137.7, 138.5, 140.5,
156.0, 158.3, 177.0. MS (%): 430 (parent+1, 100), 197 (47), 133
962). Anal. Calc'd. for C.sub.28 H.sub.31 N.sub.5 O.HCl.5/4H.sub.2
O.CH.sub.2 Cl.sub.2 : C, 56.55, H, 6.42, N, 12.21. Found: C, 56.88,
H, 6.84, N, 12.09.
EXAMPLE 60
6-(4-{2-[4-(2-Amino-ethyl)-piperazin-1-yl]-ethyl}-phenyl)-pyridin-2-ylamine
Prepared as in Example 1, using (2-amino-ethyl)-piperazine as the
t-butylcarbamate, followed by deprotection using trifluoroacetic
acid in methylene chloride, in 90% yield, as a hygroscopic solid as
the trifluoroacetate salt.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 1.93 (m, 2H), 2.3-2.5 (m, 14H),
2.81 (m, 2H), 4.50 (bs, 2H, NH), 6.40 (d, J=8, 1H), 7.03 (d, J=7,
1H), 7.23 (m, 2H), 7.45 (t, J=8, 1H), 7.81 (m, 2H). .sup.13 C-NMR
(CDCl.sub.3, .delta.): 33.3, 53.2, 60.4, 106.9, 110.7, 126.8,
128.9, 137.6, 138.3, 140.9, 156.0, 158.2. MS (%): 326 (parent+1,
8), 167 (25), 149 (100), 133 (45), 119 (28), 113 (25). HRMS.
Calc'd. for C.sub.19 H.sub.27 N.sub.5 : 326.2345. Found:
326.2340.
EXAMPLE 61
2-Amino-1-(4-{2-[4-(6-amino-pyridin-2-yl)-phenyl]-ethyl}-piperazin-1-yl)-3-
phenyl-propan-1-one
Prepared from the title compound in Example 3B, using t-BOC
henylalanine coupling mediated by N-ethyl,
N-(3-dimethylaminopropyl)carbodiimide, in 68% yield, followed by
deprotection using trifluoroacetic acid in methylene chloride in
78% yield, mp 230.degree. C. (dec.) as the hydrochloride salt from
ethyl ether.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 1.89 (m, 1H), 2.31 (m, 2H),
2.50 (m, 3H), 2.74 (m, 3H), 2.90 (m, 1H), 3.10 (m, 1H), 3.31 (m,
1H), 3.5-3.7 (m, 2H), 3.94 (m, 1H), 4.59 (bs, 2H, NH), 6.39 (d,
J=8, 1H), 7.02 (d, J=7, 1H), 7.1-7.3 (m, 7H), 7.44 (t, J=8, 1H),
7.82 (m, 2H). .sup.13 C-NMR (CDCl.sub.3, .delta.): 33.1, 41.9,
45.2, 52.5, 52.8, 59.9, 107.0, 110.6, 126.9, 128.6, 128.8, 129.4,
137.6, 137.7, 138.3, 140.5, 155.8, 158.3, 173.0. MS (%): 430
(parent+1, 23), 167 (26), 149 (100), 133 (72), 113 (25). HRMS:
Calc'd. for C.sub.26 H.sub.31 N.sub.5 O.3HCl.5/4H.sub.2 O: C,
56.19, H, 6.99, N, 11.70. Found: C, 56.55, H, 6.73, N, 11.32.
EXAMPLE 62
{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-(8-benzyl-8-aza-bicyclo[3.2.
1]oct-3-yl)-amine
Prepared as in Example 1, using
(8-benzyl-8-aza-bicyclo[3.2.1]oct-3-yl)-amine, mp 260.degree. C.
(dec.) as the hydrochloride salt.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 1.45 (m, 3H), 1.53 (m, 2H),
1.72 (m, 2H), 1.97 (m, 2H), 2.7-2.9 (m, 4H), 3.18 (m, 2H), 3.54 (s,
2H), 4.49 (bs, 2H, NH), 6.41 (d, J=8, 1H), 7.04 (d, J=7, 1H),
7.2-7.4 (m, 7H), 7.46 (t, J=8, 1H), 7.83 (m, 2H). .sup.13 C-NMR
(CDCl.sub.3, .delta.): 27.0, 36.5, 38.3, 48.1, 48.9, 55.5, 58.5,
106.9, 110.8, 126.6, 126.9, 128.1, 128.5, 128.9, 137.7, 138.3,
140.3, 140.7, 156.0, 158.2. MS (%): 413 (parent+1, 6), 200 (40),
133 (28), 91 (100). Anal. Calc'd. for C.sub.27 H.sub.32
N.sub.4.3HCl.H.sub.2 O: C, 60.06, H, 6.91, N, 10.38. Found: C,
60.33, H, 6.82, N, 10.39.
EXAMPLE 63
1-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-piperidin-4-yl)-3-phenyl-urea
Prepared as in Example 1, using 4-(phenylureido)-piperidine,
mp>280.degree. C. as the hydrochloride salt.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 1.41 (m, 2H), 1.93 (m, 2H),
2.17 (m, 2H), 2.585 (m, 2H), 2.79 (m, 2H), 2.92 (m, 2H), 3.60 (m,
1H), 6.39 (d, J=8, 1H), 6.92 (m, 2H), 7.2-7.4 (m, 7H), 7.42 (t,
J=8, 1H), 7.69 (m, 2H). .sup.13 C-NMR (CDCl.sub.3, MeOD, .delta.):
31.9, 32.8, 46.2, 52.4, 60.1, 107.3, 110.9, 119.0, 122.4, 127.0,
128.8, 137.8, 138.6, 139.3, 140.0, 155.6, 155.9, 158.5. MS (%): 416
(parent+1, 78),323 (52), 232 (50), 197 (100), 133 (82), 119 (79),
103 (69). Anal. Calc'd. for C.sub.25 H.sub.29 N.sub.5
O.2HCl.1/2H.sub.2 O.3/4CH.sub.2 Cl.sub.2 : C, 55.11, H, 6.02, N,
12.48. Found: C, 55.34, H, 6.05, N, 12.14.
EXAMPLE 64
1-(1-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-piperidin-4-yl)-3-benzyl-u
rea
Prepared as in Example 1, using 4-(benzylureido)-piperidine, in 24%
yield, mp 120.degree. C. (dec.) as the hydrochloride salt.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 1.42 (m, 2H), 1.93 (m, 2H),
2.16 (m, 2H), 2.58 (m, 2H), 2.7-2.9 (m, 4H), 3.60 (m, 1H), 4.32 (d,
J=5, 2H), 4.48 (bs, 2H, NH), 4.90 (m, 1H), 6.41 (d, J=8, 1H), 7.03
(d,J=7, 1H), 7.1-7.3 (m, 7H), 7.46 (t, J=8, 1H), 7.81 (m, 2H).
.sup.13 C-NMR (CDCl.sub.3, .delta.): 32.7, 33.4, 44.5, 47.1, 52.3,
60.2, 106.9, 110.8, 126.9, 127.3, 127.5, 128.6, 128.9, 137.7,
138.6, 139.2, 140.6, 156.0, 157.5, 158.2. MS (%): 430 (parent+1,
10), 155 (50), 135 (28), 119 (100), 103 (55). Anal. Calc'd. for
C.sub.26 H.sub.31 N.sub.5 O.2HCl.H.sub.2 O: C, 60.00, H, 6.78, N,
13.45. Found: C, 60.23, H, 6.57, N, 13.29.
EXAMPLE 65
N-(1-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-pigeridin-4-yl)-2-(4-fluor
o-phenyl)-acetamide
Prepared as in Example 1, using
4-((4-fluorophenyl)acetamido)-piperidine, in 35% yield, mp
170.degree. C. (dec.) as the hydrochloride salt.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 1.37 (m, 2H), 1.88 (m, 2H),
2.14 (m, 2H), 2.59 (m, 2H), 2.77 (m, 2H), 2.83 (m, 2H), 3.50 as,
2H), 3.79 (m, 1H), 4.46 (bs, 2H, NH), 5.23 (d, J=7, 1H), 6.42 (d,
J=8, 1H), 7.02 (m, 3H), 7.2-7.3 (m, 5H), 7.46 (dd, J=7,8, 1H), 7.81
(m, 2H). .sup.13 C-NMR (CDCl.sub.3, .delta.): 32.0, 33.5, 43.0,
46.5, 52.2, 60.2, 106.9, 110.7, 115.7, 115.95, 126.8, 128.9, 130.8,
130.9, 137.6, 138.3, 140.7, 156.0, 158.2, 170.0. MS (%): 433
(parent+1, 70), 155 (48), 119 (100), 103 (61). Anal. Calc'd. for
C.sub.26 H.sub.29 N.sub.4 OF.2HCl.3/4H.sub.2 O: C, 60.17, H, 6.31,
N, 10.80. Found: C, 60.56, H, 6.24, N, 10.75.
EXAMPLE 66
{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-(8-aza-bicyclo[3.2.
1]oct-3-yl)-amine
Prepared as in Example 1, using
N-benzyl-(8-aza-bicyclo[3.2.1]oct-3-yl)-amine followed by
debenzylation using ammonium formate and 10% palladium-on-carbon in
ethanol, in 71% yield, mp 170.degree. C. (dec.) as the
hydrochloride salt.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 1.24 (m, 2H), 1.58 (m, 2H),
1.7-1.9 (m, 4H), 2.7-2.9 (m, 4H), 3.54 (m, 2H), 4.10 (m, 1H), 4.49
(bs, 2H, NH), 6.41 (d, J=8, 1H), 7.04 (d, J=7, 1H), 7.2-7.3 (m,
2H), 7.46 (m, 1H), 7.82 (m, 2H). .sup.13 C-NMR (CDCl.sub.3,
.delta.): 29.1, 36.4, 40.7, 47.9, 19.0, 54.2, 106.9, 110.8, 126.9,
128.9, 137.7, 138.4, 140.5, 156.0, 158.2. MS (%): 323 (parent+1,
66), 199 (55), 133 (8 1), 110 (100). Anal. Calc'd. for C.sub.20
H.sub.26 N.sub.4.2HCl.2H.sub.2 O.1/4CH.sub.2 Cl.sub.2 : C, 53.73,
H, 7.24, N, 12.38. Found: C, 53.48, H, 7.23, N, 12.04.
EXAMPLE 67
6-{4-[2-(4-Amino-piperidin-1-yl)-ethyl]-phenyl}-pyridin-2-ylamine
Preparedas in Example 1, using 4-(t-butoxycarbonylamino)-piperidine
followed by deblocking with trifluoroacetic acid in methylene
chloride at room temperature, in 100% yield, mp 190-195.degree. C.
as the trifluoroacetate) salt.
.sup.1 H-NMR (TFA salt, CDCl.sub.3, .delta.): 1.99 (m, 2H), 2.28
(m, 2H), 3.17 (m, 4H), 3.41 (m, 2H), 3.50 (m, 1H), 3.78 (m, 2H),
6.96 (d, J=8, 1H), 7.14 (d, J=7, 1H), 7.52 (m, 2H), 7.78 (m, 2H),
7.95 (dd, J=7,8, 1H). .sup.13 C-NMR (CDCl.sub.3, .delta.): 28.5,
31.1, 46.7, 46.8, 51.9, 112.0, 112.9, 128.9, 131.1, 132.3, 141.3,
145.8, 148.1, 156.8. MS (%): 297 (parent+1, 100), 197 (50), 133
(52). Anal. Calc'd. for C.sub.18 H.sub.24 N.sub.4.3(C.sub.2
HF.sub.3 O.sub.2).H.sub.2 O: C, 43.91, H, 4.45, N, 8.53. Found: C,
43.82, H, 4.11, N, 8.48.
EXAMPLE 68
4-Amino-1-{2-[4-(6-amino-pyridin-2-yl)-phenyl]-ethyl}-piperidine-4-carboxyl
ic Acid Morpholine-amide
Prepared as in Example 1, using 4-amino-piperidine-4-carboxylic
acid morpholine-amide, in 13% yield, mp>280.degree. C. as the
hydrochloride salt.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 2.2-2.4 (m, 4H), 2.57 (m, 2H),
2.79 (m, 2H), 2.8-2.9 (m, 4H), 3.5-37 (m, 8H), 4.48 (bs, 2H), 6.41
(d, J=8, 1H), 7.04 (d, J=7, 1H), 7.24 (m, 2H), 7.46 (t, J=8, 1H),
7.81 (m, 2H). .sup.13 C-NMR (CDCl.sub.3, .delta.): 33.4, 34.0,
37.0, 56.4, 49.9, 60.3, 61.3, 67.1, 106.9, 110.7, 126.8, 128.9,
137.0, 138.3, 156.0, 158.2 (carbonyl carbon not visible in this
scan). MS (%): 410 (parent+1, 12), 242 (100) not--Anal. Calc'd. for
C.sub.25 H.sub.29 N.sub.5 O.2HCl.1/2H.sub.2 O.3/4CH.sub.2 Cl.sub.2
: C, 55.11, H, 6.02, N, 12.48. Found: C, 55.34, H, 6.05, N,
12.14.
EXAMPLE 69
4-Amino-1-{2-[4-(6-amino-pyridin-2-yl-phenyl]-ethyl}-piperidine-4-carboxyli
c Acid pyrrolidine-amide
Prepared as in Example 1, using 4-amino-piperidine-4-carboxylic
acid pyrrolidine-amide, in 39% yield, mp 220.degree. C. (dec.) as
the hydrochloride salt.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 1.8 (bs, 6H), 2.51 (m, 4H),
2.59 (m, 2H), 2.79 (m, 2H), 3.4-3.6 (m, 4H), 3.8 (bs, 4H), 4.51
(bs, 2H), 6.39 (d, J=8, 1H), 7.02 (d, J=7, 1H), 7.22 (m, 2H), 7.46
(t, J=8, 1H), 7.80 (m, 2H). .sup.13 C-NMR (CDCl.sub.3, .delta.):
33.4, 35.6, 45.4, 48.0, 59.8, 56.1, 60.4, 106.9, 110.7, 126.8,
128.9, 137.6, 138.3, 141.0, 156.0, 158.2, 173.8. FAB MS (%): 394
(parent+1, 28), 197 (38), 149 (63), 133 (100). Anal. Calc'd. for
C.sub.23 H.sub.31 N.sub.5 O.HCl.1/4H.sub.2 O.CH.sub.2 Cl.sub.2 : C,
55.50, H, 6.64, N, 13.48. Found: C, 55.79, H, 6.85, N, 13.10.
EXAMPLE 70
6-{4-[2-(3-Amino-pyrrolidin-1-yl)-ethyl]-phenyl}-pyridin-2-ylamine
Prepared as in Example 1, using
3-(t-butoxycarbonylamino)-pyrrolidine followed by deprotection
using trifluoroacetic acid in methylene chloride at room
temperature, in 92% yield, mp 135.degree. C. (dec.) as the
hydrochloride salt.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 1.4-1.5 (m, 3H), 2.16 (m, 1H),
2.37 (m, 1H), 2.52 (m, 1H), 2.7-2.9 (m, 6H), 3.51 (m, 1H), 4.53
(bs, 2H, NH), 6.42 (d, J=8, 1H), 7.05 (d, J=7, 1H), 7.27 (m, 2H),
7.47 (t, J=8, 1H), 7.84 (m, 2H). .sup.13 C-NMR (CDCl.sub.3,
.delta.): 35.2, 35.3, 51.0, 53.3, 58.0, 64.1, 106.8, 110.7, 126.8,
128.8, 137.6, 138.3, 141.0, 156.1, 158.2. MS (%): 283 (parent+1,
100), 197 (37), 99 (75). Anal. Calc'd. for C.sub.17 H.sub.22
N.sub.4.3HCl.H.sub.2 O: C, 49.83, H, 6.64, N, 13.67. Found: C,
49.94, H, 6.89, N, 13.29.
EXAMPLE 71
1-(3-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethylamino}-8-aza-bicyclo[3.2.
1]oct-8-yl)-2-(4-fluoro-phenyl)-ethanone
Prepared as in Example 1, using
1-amino-8-aza-bicyclo[3.2.11oct-8-yl)-2-(4-fluoro-phenyl)-ethanone,
in 23.5% yield, mp 170.degree. C. (dec.) as the hydrochloride
salt.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 1.12 (m, 1H), 1.39 (m, 1H),
1.61 (m, 2H), 1.84 (m, 4H), 2.79 (m, 4H), 2.97 (m, 1H), 3.56 (dd,
J=15,35, 2H), 4.165 (m, 1H), 4.49 (bs, 2H, NH), 4.68 (m, 1H), 6.42
(d, J=8, 1H), 6.96 (m, 2H), 7.04 (d, J=8, 1H), 7.1-7.3 (m, 4H),
7.47 (t, J=8, 1H), 7.83 (m, 2H). .sup.13 C-NMR (CDCl.sub.3,
.delta.): 27.2, 28.9, 36.3. 38.3. 39.9, 40.4, 47.9, 48.9, 51.1,
54.4, 107.0, 110.8, 115.3, 115.5, 127.0, 128.9, 130.3, 131.0,
137.9, 138.4, 140.2, 155.9, 158.2, 162.9, 1613.2. MS (%): 459
(parent+1, 27), 133 (98), 110 (100), 109 (30). Anal. Calc'd. for
C.sub.28 H.sub.31 N.sub.4 OF.2HCl.3/4H.sub.2 O: C, 61.70, H, 6.38,
N, 10.28. Found: C, 61.82, H, 6.43, N, 10.11.
EXAMPLE 72
1-(1-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-pyrrolidin-3-yl)-3-phenyl-
urea
Prepared from Example 73, using phenylisocyanate, in 53.5% yield,
mp 130.degree. C. (dec.) as the hydrochloride salt from methylene
chloride/ether.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 1.64 (m, 1H), 2.22 (m, 2H),
2.46 (m, 1H), 2.69 (m, 2H), 2.79 (m, 4H), 2.97 (m, 1H), 4.25 (bs,
1H, NH), 4.54 (bs, 2H, NH), 5.94 (bs, 1H, NH), 6.40 (d, J=8, 1H),
6.9-7.0 (m, 3H), 7.2-7.3 (m, 5H), 7.46 (t, J=8, 1H), 7.80 (m, 2H).
.sup.13 C-NMR (CDCl.sub.3, .delta.): 32.3, 34.7, 49.4, 53.1, 57.3,
61.0, 107.1, 110.8, 119.9, 122.8, 126.9, 128.8, 129.0, 137.6,
138.5, 139.3, 140.6, 155.8, 156.0, 158.4. MS (%): 402 (parent+1,
97), 197 (48), 155 (48), 133 (100), 119 (78), 103 (48). Anal.
Calc'd. for C.sub.24 H.sub.27 N.sub.5 O.2HCl.1/2C.sub.4 H.sub.10
O.1/2CH.sub.2 Cl.sub.2 : C, 57.46, H, 6.37, N, 12.64. Found: C,
57.74, H, 6.35, N, 12.44.
EXAMPLE 73
1-(1-{2-[4(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-pyrrolidin-3-yl)-3-benzyl-u
rea
Prepared from Example 73, using benzylisocyanate, in 42% yield, mp
90.degree. C. (dec.) as the hydrochloride salt from methylene
chloride/ether.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 1.65 (m, 1H), 2.19 (m, 2H),
2.45 (m, 1H), 2.6-2.8 (m, 6H), 2.95 (m, 1H), 4.17 (m, 1H), 4.28 (d,
J=6, 2H), 4.52 (m, 2H, NH), 5.27 (m, 1H), 6.40 (d, J=8, 1H), 7.01
(d, J=7, 1H), 7.2-7.3 (m, 7H), 7.45 (t, J=8, 1H), 7.79 (m, 2H).
.sup.13 C-NMR (CDCl.sub.3, .delta.): 32.4, 34.7, 44.3, 49.7, 53.0,
57.2, 61.0, 107.0, 110.7, 126.8, 127.1, 127.5, 128.5, 128.8, 137.6,
138.4, 139.5, 140.5, 155.9, 157.8, 158.2. MS (%): 416 (parent+1,
100), 197 (52), 133 (63), 119 (55), 91 (65). Anal. Calc'd. for
C.sub.21 H.sub.29 N.sub.5 O.2HCl.1/2C.sub.4 H.sub.10 O.1/2CH.sub.2
Cl.sub.2.1/2H.sub.2 O: C, 57.25, H, 6.64, N, 12.14. Found: C,
56.93, H, 6.64, N, 11.74.
EXAMPLE 74
1-(1-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-pyrrolidin-3-yl)-3-cyclohe
xyl-urea
Prepared from Example 73, using cyclohexylisocyanate, in 27% yield,
mp 120.degree. C. (dec.) as the hydrochloride salt from methylene
chloride/ether.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 1.02 (m, 3H), 1.26 (m, 3H),
1.50 (m, 1H), 1.60 (m, 3H), 1.83 (m, 2H), 2.56 (m, 1H), 2.69 (m,
2H), 2.79 (m, 2H), 2.91 (m, 1H), 3.47 (m, 1H), 4.18 (m, 1H), 5.50
(m, 1H), 6.38 (d, J=8, 1H), 6.99 (d, J=7, 1H), 7.19 (m, 2H), 7.42
(d, J=8, 1H), 7.79 (m, 2H). .sup.13 C-NMR (CDCl.sub.3, .delta.):
25.0, 25.6, 32.3, 33.9, 34.7, 48.7, 49.4, 53.1, 57.5, 61.1, 107.0,
110.6, 126.9, 128.8, 137.7, 138.3, 140.4, 155.8, 157.4, 158.4. MS
(%): 408 (parent+1, 95), 309 (62), 197 (100), 133 (61). Anal.
Calc'd. for C.sub.24 H.sub.33 N.sub.5 O.2HCl.1/2C.sub.4 H.sub.10
O.1/2CH.sub.2 Cl.sub.2.5/4H.sub.2 O: C, 54.64, H, 7.53, N, 12.02.
Found: C, 54.52, H, 7.28, N, 12.00.
EXAMPLE 75
{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-(8-methyl-8-aza-bicyclo[3.2.
1]oct-3-yl)-amine
Prepared as in Example 1, using
(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2-amine, in 27% yield, mp
98.degree. C. (dec.) as the hydrochloride salt from ether. .sup.1
H-NMR (CDCl.sub.3, .delta.): 0.9-1.9 (multiplets, 8H), 2.49 (s,
3H), 2.8-3.0 (m, 6H), 3.25 (m, 1H), 3.49 (bs, 2H, NH), 6.42 (d,
J=8, 1H), 7.02 (d, J=7, 1H), 7.23 (m, 2H), 7.46 (t, J=8, 1H), 7.81
(m, 2H). MS (%): 337 (parent+1, 100). Anal. Calc'd. for C.sub.21
H.sub.28 N.sub.4.3HCl.5/2H.sub.2 O.1/4C.sub.4 H.sub.10 O: C, 51.87,
H, 7.62, N, 11.00. Found: C, 51.87, H, 7.58, N, 10.98.
EXAMPLE 76
{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-(3-benzyl-3-aza-bicyclo[3.1.
0]hex-6-yl)-amine
Prepared as in Example 1, using
3-benzyl-3-aza-bicyclo[3.1.0]hex-6-amine, in 19% yield, as a tan
solid, as the hydrochloride salt.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 1.42 (m, 2H), 2.38 (m, 2H),
2.51 (m, 1H), 2.84 (m, 2H), 2.94 (m, 4H), 3.55 (s, 2H), 4.52 (bs,
2H, NH), 6.41 (d, J=8, 1H), 7.04 (d, J=8, 1H), 7.2-7.3 (m, 7H),
7.46 (t, J=8, 1H), 7.83 (m, 2H). .sup.13 C-NMR (CDCl.sub.3,
.delta.): 24.3, 35.7, 38.7, 50.5, 54.4, 59.1, 106.9, 110.7, 126.8,
126.9, 128.2, 128.6, 128.9, 137.7, 138.4, 139.5, 140.4, 156.0,
158.2. MS (%): 385 (parent+1, 20), 155 (64), 119 (100). not--Anal.
Calc'd. for C.sub.23 H.sub.31 N.sub.5 O.HCl.1/4H.sub.2 O.CH.sub.2
Cl.sub.2 : C, 55.50, H, 6.64, N, 13.48. Found: C, 55.79, H, 6.85,
N, 13.10.
EXAMPLE 77
{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-[8-(4-fluoro-benzyl)-8-aza-bicy
clo[3.2.1]oct-3-yl]-amine
Prepared as in Example 1, using
8-(4-fluoro-benzyl)-8-aza-bicyclo[3.2.1]oct-3-amine, in 22% yield,
mp 190.degree. C. (dec.) as the hydrochloride salt.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 1.43 (m, 2H), 1.52 (m, 2H),
1.70 (m, 2H), 1.95 (m, 2H), 2.7-2.8 (m, 5H), 3.14 (m, 2H), 3.50 (s,
2H), 4.49 (bs, 2H, NH), 6.41 (d, J=8, 1H), 6.94 (m, 2H), 7.04 (d,
J=8, 1H), 77.24 (m, 2H), 7.30 (m, 2H), 7.46 (t, J=8, 1H), 7.83 (m,
2H). .sup.13 C-NMR (CDCl.sub.3, .delta.): 27.0, 36.4, 38.3, 48.0,
48.9, 54.8, 58.3, 106.9, 110.7, 114.7, 114.9, 126.7, 126.8, 126.9,
128.9, 129.8, 129.9, 135.9, 137.8, 138.3, 140.6, 156.0, 158.2,
160.5, 162.9. MS (%): 431 (parent+1, 44), 218 (56), 109 (100).
Anal. Calc'd. for C.sub.27 H.sub.31 N.sub.4 F.3HCl.3/2H.sub.2 O: C,
57.20, H, 6.58, N, 9.88. Found: C, 57.30, H, 6.91, N, 9.56.
EXAMPLE 78
{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-[8-(4-chloro-benzyl)-8-aza-bicy
clo[3.2.1]oct-3-yl]-amine
Prepared as in Example 1, using
8-(4-chloro-benzyl)-8-aza-bicyclo[3.2.1]oct-3-amine, in 29% yield,
mp 198.degree. C. (dec.) as the hydrochloride salt.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 1.42 (m, 2H), 1.52 (m, 2H),
1.68 (m, 2H), 1.94 (m, 2H), 2.8-2.9 (m, 5H), 3.13 (bs, 2H), 3.49
(s, 2H), 4.53 (bs, 2H, NH), 6.40 (d, J=8, 1H), 7.03 (d, J=7, 1H),
7.2-7.3 (m, 7H), 7.45 (t, J=8, 1H), 7.82 (m, 2H). .sup.13 C-NMR
(CDCl.sub.3, .delta.): 24.0, 36.2, 37.9, 47.9, 49.0, 54.8, 58.1,
107.0, 110.7, 126.8, 127.0, 128.2, 128.3, 128.9, 129.8, 130.0,
132.2, 137.8, 138.4, 138.7, 140.4, 156.0, 158.2. MS (%): 447
(parent+1, 45), 234 (54), 125 (100). Anal. Calc'd. for C.sub.27
H.sub.31 N.sub.4 Cl.3HCl.1/2H.sub.2 O: C, 57.36, H, 6.24, N, 9.91.
Found: C, 57.27, H, 6.44, N, 9.57.
EXAMPLE 79
4-Amino-1-{2-[4-(6-amino-pyridin-2-yl)-phenyl]-ethyl}-piperidine-4-carboxyl
ic Acid phenethyl-amide
Prepared as in Example 1, using 4-amino-piperidine-4-carboxylic
acid phenethyl-amide, in 12% yield, mp 215-219.degree. C. (dec.) as
the hydrochloride salt.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 1.31 (m, 2H), 1.80 (bs, 2H),
2.25 (m, 4H), 2.62 (m, 2H), 2.8-3.0 (m, 6H), 3.48 (m, 2H), 4.49
(bs, 2H, NH), 6.41 (d, J=8, 1H), 7.04 (d, J=7, 1H), 7.2-7.4 (m,
7H), 7.46 (t, J=8, 1H), 7.82 (m, 2H). .sup.13 C-NMR (CDCl.sub.3,
.delta.): 33.4, 35.0, 35.8, 40.4, 49.0, 55.2, 60.4, 106.9, 110.7,
126.4, 126.8, 128.5, 128.8, 128.9, 137.6, 138.3, 139.1, 140.9,
156.0, 158.2, 176.9. MS (%): 444 (parent+1, 15), 197 (54), 133
(100). Anal. Calc'd. for C.sub.27 H.sub.33 N.sub.5 O.3HCl: C,
58.65, H, 6.56, N, 12.66. Found: C, 58.29, H, 6.97, N, 12.28.
EXAMPLE 80
3-{2-[4-(6-Amino-pyridin-1-yl)-phenyl-ethylamino}-pyrrolidine-1-carboxylic
Acid phenylamide
Prepared as in Example 1, using 3-amino-pyrrolidine-1-carboxylic
acid phenylamide, in 8% yield, mp 130.degree. C. (dec.) as the
hydrochloride salt from ethyl ether.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 1.64 (m, 1H), 2.20 (m, 2H),
2.46 (dd, J=3,7, 1H), 2.66 (m, 2H), 2.78 (m, 4H), 2.97 (m, 1H),
4.25 (bs, 1H, NH), 4.53 (bs, 2H, NH), 5.85 (d, J=7, 1H), 6.40 (d,
J=8, 1H), 6.9-7.0 (m, 3H), 7.2-7.3 (m, 5H), 7.46 (t, J=8, 1H), 7.79
(m, 2H). .sup.13 C-NMR (CDCl.sub.3, .delta.): 32.4, 34.8, 49.6,
53.1, 57.3, 61.0, 107.1, 110.8, 120.0, 122.9, 126.9, 128.8, 129.0,
137.6, 138.4, 139.2, 140.7, 155.6, 156.0, 158.3. MS (%): 402
(parent+1, 100), 283 (20), 264 (18). Anal. Calc'd. for C.sub.24
H.sub.27 N.sub.5 O.2HCl.H.sub.2 O.C.sub.4 H.sub.10 O: C, 59.36, H,
7.29, N, 12.36. Found: C, 59.34, H, 6.69, N, 12.59.
EXAMPLE 81
(3-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethylamino}-pyrrolidin-1-yl)-phenyl
-methanone
Prepared as in Example 1, using
3-amino-pyrrolidin-1-yl-phenyl-methanone, in 10% yield, mp
130.degree. C. (dec.) as the hydrochloride salt from ethyl
ether.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 1.71 (m, 1H), 1.98 and 2.13
(multiplets, 1H), 2.7-3.0 (m, 3H), 3.2-3.8 (multiplets, 6H), 4.51
(bs, 2H, NH), 6.42 (d, J=8, 1H), 7.04 (t, J=7, 1H), 7.20 (d, J=8,
1H), 7.26 (m, 1H), 7.38 (m, 3H), 7.46 (m, 3H), 7.83 (m, 2H).
.sup.13 C-NMR (CDCl.sub.3, .delta.): 30.8, 32.5, 36.0, 44.7, 47.8,
49.2, 49.3, 52.1, 55.1, 56.3, 57.9, 107.0, 110.75, 127.0, 127.1,
128.2, 128.3, 128.9, 129.9, 137.9, 138.4, 140.0, 155.8, 158.2,
169.8. MS (%): 387 (parent+1, 75), 155 (44), 119 (100), 105 (60).
Anal. Calc'd. for C.sub.24 H.sub.26 N.sub.4 O.HCl.1/2CH.sub.2
Cl.sub.2.C.sub.4 H.sub.10 O: C, 63.44, H, 7.10, N, 10.38. Found: C,
63.33, H, 6.72, N, 10.39.
EXAMPLE 82
6-{4-[2-(1-Benzyl-pyrrolidin-3-ylamino)-ethyl]-phenyl}-pyridin-2-ylamine
Prepared as in Example 1, using 1-benzyl-pyrrolidin-3-ylamine, in
27% yield, mp 145.degree. C. (dec.) as the hydrochloridel salt.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 1.49 (m, 1H), 2.08 (m, 1H),
2.26 (dd, J=5,9, 1H), 2.73 m, 1H), 2.81 (s, 4H), 3.29 (m, 1H), 3.56
(AB.sub.q, J=19, Dn=13, 2H), 4.52 (bs, 2H, NH), 6.39 (d, J=8, 1H),
7.04 (d, J=7, 1H), 7.28 (m, 7H), 7.45 (t, J=8, 1H), 7.83 (m, 2H).
.sup.13 C-NMR (CDCl.sub.3, .delta.): 32.1, 36.3, 49.5, 53.0, 57.3,
60.5, 60.7, 106.9, 110.7, 126.88, 126.94, 128.2, 128.8, 128.9,
137.8, 138.3, 139.0, 140.5, 156.0, 158.3. MS (%): 373 (parent+1,
100), 155 (35), 119 (78), 103 (35). Anal. Calc'd. for C.sub.24
H.sub.28 N.sub.4.3HCl.1/2H.sub.2 O: C, 58.72, H, 6.57, N, 11.41.
Found: C, 58.37, H, 6.67, N, 11.23.
EXAMPLE 83
N-(8-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-8-aza-bicyclo[3.2.
1]oct-3-yl)-benzamide
Prepared as in Example 1, using
8-aza-bicyclo[3.2.1]oct-3-yl)-benzamide, in 29% yield, mp 211
.degree. C. (dec.) as the hydrochloride salt.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 1.67 (m, 2H), 1.78 (m, 2H),
1.92 (m, 2H), 2.00 (m, 2H), 3.39 (m, 2H), 4.36 (m, 1H), 4.47 (bs,
2H, NH), 5.96 (d, J=8, 1H), 6.42 (d, J=8, 1H), 7.04 (d, J=8, 1H),
7.26 (m, 2H), 7.40 (m, 2H), 7.47 (m, 2H), 7.70 (m, 2H), 7.82 (m,
2H). .sup.13 C-NMR (CDCl.sub.3, .delta.): 26.4, 35.4, 37.65, 41.6,
53.8, 59.2, 106.9, 110.7, 126.8, 128.5, 128.9, 131.4, 134.7, 137.7,
138.3, 140.7, 156.0, 158.2, 166.7. MS (%): 427 (parent+1, 100).
Anal. Calc'd. for C.sub.27 H.sub.30 N.sub.4.2HCl.H.sub.2 O: C,
62.67, H, 6.62, N, 10.83. Found: C, 62.85, H, 6.57, N, 10.52.
EXAMPLE 84
{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-(3-benzyl-3-aza-bicyclo[3.3.
1]non-9-yl)-amine
Prepared as in Example 1, using
(3-benzyl-3-aza-bicyclo[3.3.1]non-9-yl)-amine, in 24% yield, mp
190.degree. C. (dec.) as the hydrochloride salt, as a mixture of
endo and exo isomers.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 1.44 (m, 2H), 1.76 (m, 4H),
2.37 (m, 2H), 2.55 (m, 2H), 2.86 (s, 4H), 2.94 (m, 2H), 3.28 and
3.27 (singlets, 2H, endo and exo isomers in roughly 1:1 ratio,
N-benzyl CH.sub.2 group), 4.47 (bs, 2H, NH), 6.44 (dd, J=2,8, 1H),
7.07 (dd, J=3,7, 1H), 7.1-7.3 (m, 7H), 7.47 (dt, J=2,8, 1H), 7.86
(m, 2H). .sup.13 C-NMR (CDCl.sub.3, .delta.): 21.2, 24.5, 32.3,
33.0, 47.8, 53.1, 60.2, 63.5, 63.8, 106.9, 110.7, 126.2, 126.6,
126.9, 128.1, 128.2, 128.6, 128.7, 128.9, 129.0, 138.3, 139.0,
141.0, 158.0, 159.0. MS (%): 427 (parent+1, 68), 91 (100). Anal.
Calc'd. for C.sub.28 H.sub.34 N.sub.4.3HCl.1/2H.sub.2 O: C, 61.71,
H, 7.03, N, 10.28. Found: C, 61.86, H, 7.19, N, 9.97.
EXAMPLE 85
N-(8-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-8-aza-bicyclo[3.2.
1]oct-3-yl)-2-(4-fluoro-phenyl)-acetamide
Prepared as in Example 1, using
8-aza-bicyclo[3.2.1]oct-3-yl)-2-(4-fluoro-phenyl)-acetamide, in 23%
yield, mp 160.degree. C. (dec.) as the hydrochloride salt.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 1.49 (m, 2H), 1.69 (m, 2H),
1.76 (m, 2H), 1.93 (m, 2H), 2.58 (m, 2H), 2.81 (m, 2H), 3.33 (bs,
2H), 3.44 (s, 2H), 3.49 (s, 1H), 4.13 (m, 1H), 4.49 (bs, 2H, NH),
6.41 (d, J=8, 1H), 7.01 (m, 3H), 7.21 (m, 4H), 7.45 (t, J=8, 1H),
7.81 (m, 2H). .sup.13 C-NMR (CDCl.sub.3, .delta.): 26.1, 35.1,
37.6, 37.8, 41.0, 42.9, 52.9, 54.0, 59.4, 107.0, 110.7, 115.7,
115.9, 126.9, 127.3, 128.9, 129.0, 129.4, 130.9, 137.8, 138.4,
140.3, 155.9, 158.2, 170.1. MS (%): 459 (parent+1, 100), 197 (21),
119 (31), 103 (36). Anal. Calc'd. for C.sub.28 H.sub.31 N.sub.4
FO.2HCl.1/2H.sub.2 O: C, 62.22, H, 6.34, N, 10.37. Found: C, 61.99,
H, 6.50, N, 10.01.
EXAMPLE 86
6-{4-[2-(3-Amino-piperidin-1-yl)-ethyl]-phenyl}-pyridin-2-ylamine
Preparedas in Example 1, using
3-(t-butoxycarbonylamino)-piperidine, in 100% yield following
condensation with (6-amino-pyridin-2-yl)-phenyl]-2-chloroethane and
deblocking with trifluoroacetic acid in methylene chloride, mp
150.degree. C. (dec.) as the hydrochloride salt.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 1.20 (m, 1H), 1.42 (m, 1H),
1.62 (m, 1H), 1.85 (m, 1H), 2.31 (td, J=2,9, 1H), 2.51 (m, 2H),
2.79 (m, 2H), 2.86 (m, 3H), 3.08 (m, 1H), (bs, 2H, NH), 6.39 (dd,
J=1,8, 1H), 7.02 (dd, J=1,7, 1H), 7.23 (m, 2H), 7.44 (td, J=1,8,
1H), 7.81 (m, 2H). .sup.13 C-NMR (CDCl.sub.3, .delta.): 25.1, 31.8,
36.3, 46.6, 48.1, 52.4, 54.75, 106.9, 110.7, 126.9, 128.9, 137.7,
138.3, 140.5, 156.0, 158.2. MS (%): 297 (parent+1, 57), 135 (40),
119 (100), 103 (62). Anal. Calc'd. for C.sub.18 H.sub.24
N.sub.4.3HCl.H.sub.2 O.1/2CH.sub.2 Cl.sub.2 : C, 51.70, H, 6.80, N,
13.03. Found: C, 51.90, H, 6.64, N, 12.59.
EXAMPLE 87
N-(3-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-3-aza-bicyclo[3.3.
1]non-9-yl)-benzamide, Anti-isomer
Prepared as in Example 1, using
3-aza-bicyclo[3.3.1]non-9-yl)-benzamide, anti-isomer, in 18% yield,
mp 185.degree. C. (dec.) as the hydrochloride salt.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 1.35 (m, 1H), 1.71 (m, 4H),
1.95 (m, 2H), 2.4-2.5 (m, 5H), 2.79 (m, 2H), 3.04 (m, 2H), 4.10 (m,
1H), 4.53 (bs, 2H, NH), 6.41 (dd, J-1,8, 1H), 6.42 (m, 1H), 7.05
(dd, J=1,7, 1H), 7.25 (m, 2H), 7.4-7.5 (m, 4H), 7.75 (m, 2H), 7.84
(m, 2H). .sup.13 C-NMR (CDCl.sub.3, .delta.): 20.6. 25.3, 32.9,
33.5, 51.4, 59.5, 59.9, 106.8, 110.6, 126.6, 126.8, 128.6, 158.9,
131.3, 135.1, 137.3, 138.3, 141.5, 156.1, 158.2, 166.9. MS (%): 441
(parent+1, 41), 149 (75), 119 (100). Anal. Calc'd. for C.sub.28
H.sub.32 N.sub.4 O.2HCl.1/2H.sub.2 O.1/4(C.sub.4 H.sub.10 O): C,
64.38, H, 6.99, N, 10.36. Found: C, 64.49, H, 6.43, N, 9.91.
EXAMPLE 88
N-(3-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-3-aza-bicyclo[3.3.
1]non-9-yl)-benzamide, Syn-isomer
Prepared as in Example 1, using
3-aza-bicyclo[3.3.1]non-9-yl)-benzamide, syn-isomer, in 9% yield,
as a hygroscopic solid as the hydrochloride salt.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 1.37 (m, 1H), 1.81 (m, 4H),
2.00 (m, 2H), 2.33 (m, 1H), 2.51 (m, 4H), 2.83 (m, 4H), 4.04 (m,
1H), 4.48 (bs, 2H, NH), 6.42 (dd, J=1,8, 1H), 7.05 (dd, J=1,7, 1H),
7.24 (m, 2H), 7.4-7.5 (m, 4H), 7.74 (m, 2H), 7.82 (m, 2H). .sup.13
C-NMR (CDCl.sub.3, .delta.): 20.3, 31.9, 33.4, 33.7, 50.8, 53.8,
60.5, 107.1, 110.7, 126.7, 126.8, 128.6, 128.9, 131.3, 135.1,
137.0, 138.6, 141.4, 155.6, 158.1, 166.6. MS (%): 441 (parent+1,
5), 391 (10), 167 (23), 149 (100). Anal. Calc'd. for C.sub.28
H.sub.32 N.sub.4 O.HCl.1/2CH.sub.2 Cl.sub.2.1/2(C.sub.4 H.sub.10
O): C, 65.82, H, 7.06, N, 10.07. Found: C, 66.20, H, 6.80, N,
10.10.
EXAMPLE 89
6-{4-[2-(4-Benzhydryl-piperazin-1-yl)-ethyl]-phenyl}-pyridin-2-ylamine
Prepared as in Example 1, using 4 benzhydryl-piperazine, in 54%
yield, mp 170.degree. C. (dec.) as the hydrochloride salt.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 2.45 (m, 4H), 2.56 (m, 4H),
2.61 (m, 2H), 2.82 (m, 2H), 4.24 (s, 1H), 4.54 (bs, 2H, NH), 6.37
(d, J=8, 1H), 7.04 (d, J=8, 1H), 7.19 (m, 2H), 7.26 (m, 6H), 7.42
(m, 5H), 7.85 (m, 2H). .sup.13 C-NMR (CDCl.sub.3, .delta.): 33.4,
51.9, 52.0, 53.5, 60.4, 106.8, 110.6, 126.8, 126.9, 128.0, 128.5,
128.9, 137.6, 138.3, 141.0, 142.8, 156.0, 158.3. MS (%): 449
(parent+1, 17), 253 (12), 167 (100), 149 (14). Anal. Calc'd. for
C.sub.30 H.sub.32 N.sub.4.2HCl.1/4CH.sub.2 Cl.sub.2 : C, 66.94, H,
6.41, N, 10.32. Found: C, 66.57, H, 6.22, N, 10.17.
EXAMPLE 90
6-{4-[2-(4-Benzhydryl-piperidin-1-yl)-ethyl]-phenyl}-pyridin-2-ylamine
Prepared as in Example 1, using 4-benzhydryl-piperidine, in 24%
yield, mp 175.degree. C. (dec.) as the hydrochloride salt.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 1.32 (m, 2H), 1.56 (m, 2H),
2.11 (m, 2H), 2.14 (m, 1H), 2.61 (m, 2H), 2.83 (m, 2H), 2.99 (m,
2H), 3.50 (d, J=11, 1H), 4.46 (bs, 2H, NH), 6.41, (dd, J=0.5,8,
1H), 7.04 (dd, J=0.5,7.5, 1H), 7.14 (m, 2H), 7.2-7.3 (m, 10H), 7.46
(t, J=8, 1H), 7.82 (m, 2H). .sup.13 C-NMR (CDCl.sub.3, .delta.):
31.2, 33.4, 39.5, 53.9, 58.9, 60.6, 106.9, 110.7, 126.2, 126.8,
128.0, 128.5, 128.9, 138.3, 143.7, 156.0, 158.2. MS (%): 448
(parent+1, 100), 264 (32), 149 (70). Anal. Calc'd. for C.sub.31
H.sub.33 N.sub.3.2HCl.1/4CH.sub.2 Cl.sub.2 : C, 69.28, H, 6.60, N,
7.76. Found: C, 68.96, H, 6.48, N, 7.36.
EXAMPLE 91
3-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-3-aza-bicyclo[3.3.
1]non-9-ylamine
Prepared as in Example 1, using 3-aza-bicyclo[3.3.1]non-9-ylamine
t-butylcarbamate followed by deprotection using trifluoroacetic
acid in methylene chloride in 85% yield, as a low-melting solid as
the hydrochloride salt.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 1.28 (m, 1H), 1.48 (m, 2H),
1.61 (bs, 2H), 1.82 (m, 2H), 2.26 (m, 2H), 2.35 (m, 1H), 2.46 (t,
J=7, 2H), 2.78 (m, 3H), 3.02 (m, 2H, 4.46 (bs, 2H, NH), 6.41 (dd,
J=0.5,8, 1H), 7.05 (d, J=0.6,7, 1H), 7.24 (m, 2H), 7.46 (t, J=8,
1H), 7.82 (m, 2H). .sup.13 C-NMR (CDCl.sub.3, .delta.): 20.9, 24.1,
33.7, 36.1, 52.8, 60.2, 106.7, 110.7, 126.6, 128.9, 137.2, 138.3,
141.7, 156.2, 158.1. MS (%): 337 (parent+1, 13), 279 (14), 167
(30), 149 (100), 113 (39). Anal. Calc'd. for C.sub.21 H.sub.28
N.sub.4.2HCl.1/2CH.sub.2 Cl.(C.sub.4 H.sub.10 O): C, 58.23, H,
7.86, N, 10.65. Found: C, 58.15, H, 7.31, N, 10.72.
EXAMPLE 92
3-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-3-aza-bicyclo[3.1.
0]hexane-6-carboxylic Acid Ethyl Ester
Prepared as in Example 1, using
3-aza-bicyclo[3.1.0]hexane-6-carboxylic acid ethyl ester in 18%
yield, as a low melting solid as the hydrochloride salt.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 1.23 (t, J=7, 3H), 1.93 (bs,
2H), 1.99 (bs, 1H), 2.40 (d, J=9, 1H), 2.65 (m, 2H), 2.71 (m, 2H),
3.12 (d, J=9, 2H), 4.49 (bs, 2H, NH), 6.40 (d, J=8, 1H), 7.04 (d,
J=7.5, 1H), 7.21 (m, 2H), 7.45 (t, J=7.5, 1H), 7.81 (m, 2H).
.sup.13 C-NMR (CDCl.sub.3, .delta.): 14.3, 21.8, 26.3, 35.1, 54.4,
56.4, 30.2, 106.8, 110.7, 126.7, 128.8, 137.5, 138.3, 141.0, 156.1,
158.2, 173.9. MS (%): 352 (parent+1, 5), 167 (22), 149 (100), 113
(20). Anal. Calc'd. for C.sub.21 H.sub.25 N.sub.3 O.sub.2.2HCl: C,
H, N. Found: C, H, N.
EXAMPLE 93
3-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-3-aza-bicyclo[3.1.
0]hexane-6-carboxylic Acid
Prepared by hydrolysis of Example 92 using 2N hydrochloric acid at
70.degree. C. for 8 h in 83% yield, as a low-melting solid as the
hydrochloride salt.
.sup.1 H-NMR (HCl salt, CDCl.sub.3, .delta.): 2.18 (s, 2H), 2.31
(m, 2H), 3.28 (s, 1H), 3.4-3.6 (m, 4H), 3.89 (m, 2H), 6.96 (m, 1H),
7.15 (m, 1H), 7.53 (m, 2H), 7.79 (m, 2H), 7.94 (m, 1H). .sup.13
C-NMR (CDCl.sub.3, .delta.): 24.3, 29.2, 31.5, 38.8, 55.7, 110.7,
111.6, 124.7, 127.6, 128.5, 130.0, 130.6, 131.0, 140.0, 144.6,
146.4, 155.4, 167.9. MS (%): 324 (parent+1, 23), 279 (11), 167
(25), 149 (100), 129 (12), 113 (27). HRMS Calc'd. for C.sub.19
H.sub.22 N.sub.3 O.sub.2 (parent+1): 324.1712. Found: 324.1717.
EXAMPLE 94
3-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethylamino}-piperidine-1-carboxylic
Acid tert-butyl Ester
Prepared as in Example 1, using piperidine-1-carboxylic acid
tert-butyl ester in 29% yield as a foam.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 1.43 (s, 9H), 1.6-1.8 (m, 3H),
2.35 (m, 2H), 2.54 (m, 3H), 2.76 (t, J=8, 2H), 3.74 (m, 1H), 4.55
(bs, 2H), 5.03 (bs, 1H), 6.39 (d, J=8, 1H), 7.03 (d, J=7, 1H), 7.22
(m, 2H), 7.44 (t, J=8, 1H), 7.83 (m, 2H). .sup.13 C-NMR
(CDCl.sub.3, .delta.): 22.3, 28.5, 29.7, 33.3, 46.3, 53.8, 58.5,
60.3, 78.9, 106.8, 110.6, 126.8, 128.9, 13.5, 138.3, 141.0, 155.2,
156.0, 158.3. MS (%): 397 (parent+1, 56), 297 (38), 280 (48), 213
(40), 197 (95), 157 (100). HRMS Calc'd. for C.sub.23 H.sub.33
N.sub.4 O.sub.2 (parent+1): 397.26035. Found: C, 397.2581.
EXAMPLE 95
6-{4-[2-(Piperidin-3-ylamino)-ethyl]-phenyl}-pyridin-2-ylamine
Prepared by deprotection of Example 94 using trifluoroacetic acid
in methylene chloride in 92% yield, as the hydrochloride salt from
ethyl ether.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 1.35 (bs, 2H), 1.58 (m, 1H),
1.69 (m, 1H), 1.85 (m, 1H), 2.07 (m, 1H), 2.60 (m, 2H), 2.74 (m,
1H), 2.79 (m, 2H), 2.81 (m, 4H), 4.47 (bs, 2H), 6.41 (d, J=8, 1H),
7.04 (d, J=8, 1H), 7.23 (m, 2H), 7.46 (t, J=8, 1H), 7.82 (m, 2H).
.sup.13 C-NMR (CDCl.sub.3, .delta.): 23.8, 33.3, 34.2, 48.1, 53.6,
60.6, 62.7, 106.8, 110.7, 126.8, 128.9, 137.5, 138.3, 141.1, 156.0,
158.2. FAB MS (%): 297 (parent+1, 12), 167 925), 149 (100), 119
(27), 111 (25). Anal. Calc'd. for C.sub.18 H.sub.24
N.sub.4.3HCl.H.sub.2 O.1/4(C.sub.4 H.sub.10 O): C, 51.59, H, 7.18,
N, 12.67, Found: C, 51.86, H, 7.23, N, 12.31.
EXAMPLE 96
6-{4-[2-(1-Benzyl-piperidin-4-ylamino)-ethyl]-phenyl}-pyridin-2-ylamine
Prepared as in Example 1, using 1-benzyl-4-aminopiperidine in 82%
yield (purification was effected by forming the t-butylcarbamate
derivative followed by chromatography and deprotection with
trifluoroacetic acid in methylene chloride), as the hydrochloride
salt.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 1.38 (m, 2H), 1.80 (m, 2H),
1.99 (m, 2H), 2.46 (m, 1H), 2.83 (m, 4H), 2.90 (m, 2H), 3.48 (s,
2H), 4.57 (bs, 2H), 6.40 (d, J=8, 1H), 7.05 (d, J=7, 1H), 7.30 (m,
7H), 7.45 (t, J=8, 1H), 7.85 (m, 2H). .sup.13 C-NMR (CDCl.sub.3,
.delta.): 32.7, 36.3, 48.0, 52.5, 54.9, 36.1, 106.9, 110.7, 126.9,
128.2, 128.9, 129.1, 137.8, 138.3, 138.6, 140.6, 156.0, 158.3. FAB
MS (%): 387 (parent+1, 47), 174 (31), 149 (100), 119 (97), 103
(52). HRMS Calc'd. for C.sub.25 H.sub.30 N.sub.4 : 387.2548. Found:
387.2582.
EXAMPLE 97
3-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-3-aza-bicyclo[3.1.
0]hex-6-ylamine (anti-isomer)
Prepared is in Example 1, using 3-aza-bicyclo[3.1.0]hex-6-ylamine
(anti-isomer) t-butylcarbarnate followed by deprotection using
trifluoroacetic acid in methylene chloride in 79% yield, as the
hydrochloride salt from ethyl ether.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 1.34 (m, 2H), 1.90 (bs, 2H),
2.29 (t, J=7,1H), 2.63 (m, 2H), 2.69 (m, 2H), 2.76 (m, 2H), 3.09
(d, J=9, 2H), 4.52 (bs, 2H), 6.41 (d, J=8, 1H), 7.04 (d, J=8, 1H),
7.22 (m, 2H), 7.45 (t, J=8, 1H), 7.82 (m, 2H). .sup.13 C-NMR
(CDCl.sub.3, .delta.): 19.9, 34.4, 35.4, 52.7, 57.0, 106.8, 110.7,
126.7, 128.8, 137.5, 138.3, 141.2, 156.1, 158.2. FAB MS (%): 295
(parent+1, 3), 279 (10), 167 (20), 149 (100), 129 (6), 113 (25).
Anal. Calc'd. for C.sub.18 H.sub.22 N.sub.4.2HCl.1/4CH.sub.2
C.sub.2.1/2(C.sub.4 H.sub.10 O).5/4H.sub.2 O: C, 54.27, H, 7.20, N,
12.50. Found: C, 53.92, H, 6.83, N, 12.19.
EXAMPLE 98
6-{4-[2-(Piperidin-4-ylamino)-ethyl]-phenyl}-pyridin-2-ylamine
Prepared by deblocking Example 96 using ammonium formate and 10%
palladium-on-carbon in refluxing ethanol in 67.5% yield, as the
hydrochloride salt from ethyl ether.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 1.30 (m, 2H), 1.87 (m, 2H),
2.65 (m, 3H), 2.81 (m, 2H), 2.88 (m, 2H), 3.13 (m, 2H), 4.54 (bs,
2H), 6.42 9d, J=8, 1H), 7.04 (d, J=8, 1H), 7.25 (m, 2H), 7.46 (t,
J=8, 1H), 7.83 (m, 2H). .sup.13 C-NMR (CDCl.sub.3, .delta.): 32.3,
36.1, 44.2, 47.7, 53.9, 107.0, 110.7, 127.0, 128.9, 137.8, 138.4,
140.3, 155.95, 158.3. MS (%): 297 (parent+1, 10), 199 (35), 149
(100), 119 (30). Anal. Calc'd. for C.sub.18 H.sub.24
N.sub.4.3HCl.1/4CH.sub.2 Cl.sub.2 1/2(C.sub.4 H.sub.10 O): C,
53.70, H, 7.32, N, 12.52. Found: C, 53.61, H, 6.99, N, 12.18.
EXAMPLE 99
6-(4-{2-[(Piperidin-4-ylmethyl)-amino]-ethyl}-phenyl)-pyridin-2-ylamine
Prepared as in Example 1, using
4-aminomethylpiperidine-1-t-butylcarbamate followed by deprotection
using trifluoroacetic acid in methylene chloride in 80.5% yield, as
the hydrochloride salt.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 1.25 (m, 3H), 1.87 (m, 2H),
2.65 (m, 2H), 2.81 (m, 2H), 2.88 (m, 2H), 3.13 (m, 2H), 4.54 (bs,
2H), 6.42 (d, J=8, 1H), 7.04 (d, J=8, 1H), 7.26 (m, 2H), 7.46 (t,
J=8, 1H), 7.83 (m, 2H). .sup.13 C-NMR (CDCl.sub.3, .delta.): 32.3,
36.1, 44.2, 47.7, 53.9, 107.0, 110.7, 127.0, 128.9, 137.8, 138.4,
140.3, 155.95, 158.3. FAB MS (%): 297 (parent+1, 16), 199 (35), 149
(100), 119 (30). Anal. Calc'd. for C.sub.19 H.sub.26
N.sub.4.3HCl7/4H.sub.2 O.3/4(C.sub.4 H.sub.10 O): C, 52.12, H,
7.95, N, 11.05. Found: C, 52.62, H, 7.59, N, 10.96.
EXAMPLE 100
(3-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-3-aza-bicyclo[3.1.
0]hex-6-yl)-(4-methyl-piperazin-1-yl)-methanone
Prepared as in Example 1, using
3-aza-bicyclo[3.1.0]hex-6-yl)-(4-methyl-piperazin-1-yl)-methanone
in 14% yield, as the hydrochloride salt.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 1.94 (bs, 2H), 2.09 (bs, 1H),
2.2-2.4 (m, 8H), 2.27 (s, 3H), 2.68 (m, 2H), 2.73 (m, 2H), 3.11 (m,
2H), 3.61 (m, 4H), 4.49 (bs, 2H), 6.41 (d, J=8, 1H), 7.03 (d, J=8,
1H), 7.21 (m, 2H), 7.45 (t, J=8, 1H), 7.81 (m, 2H). .sup.13 C-NMR
(CDCl.sub.3, .delta.): 19.7, 25.6, 35.1, 41.8, 45.5, 46.0, 54.5,
54.7, 55.3, 56.7, 106.9, 110.7, 126.7, 1228.8, 137.5, 138.3, 140.9,
156.0, 158.0, 171.1. MS (%): 406 (parent+1, 3), 391 (20), 167 (18),
149 (100), 113 (19). Anal. Calc'd. for C.sub.24 H.sub.31 N.sub.5
O.3HCl.2H.sub.2 O.5/4(C.sub.4 H.sub.10 O): C, 54.12, H, 7.91, N,
10.88. Found: C, 53.97, H, 7.57, N, 10.56.
EXAMPLE 101
{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-(9-benzyl-3-oxa-9-aza-bicyclo[3
.3.1]non-7-yl)-amine (more polar diastereomer)
Prepared as in Example 1, using
(9-benzyl-3-oxa-9-aza-bicyclo[3.3.1]non-7-yl)-amine, more polar
diastereomer, in 38% yield, as a foam as the hydrochloride
salt.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 1.52 (m, 2H), 2.26 (m, 2H),
2.56 (m, 2H), 2.88 (m, 4H), 2.97 (m, 1H), 3.47 (m, 2H), 3.79 (s,
2H), 3.82 (m, 2H), 4.50 (bs, 2H), 6.41 (d, J=8, 1H), 7.05 (d, J=8,
1H), 7.2-7.4 (m, 7H), 7.46 (t, J=8, 1H), 7.83 (m, 2H). .sup.13
C-NMR (CDCl.sub.3, .delta.): 27.4, 36.7, 48.4, 49.0, 50.8, 56.1,
69.5, 106.8, 110.7, 126.7, 127.0, 128.3, 128.5, 128.9, 137.5,
138.3, 139.0, 141.2, 156.1, 158.2. MS (%): 429 (parent+1, 42), 216
(53), 91 (100).
Anal. Calc'd. for C.sub.27 H.sub.32 N.sub.4 O.3HCl.H.sub.2 O: C
58.33, H 4.71, N 10.08. Found: C 58.12, H 6.82, N 9.83.
EXAMPLE 102
{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-(9-benzyl-3-oxa-9-aza-bicyclo[3
.3.1]non-7-yl)-amine (less polar diastereomer)
Prepared as in Example 1, using
(9-benzyl-3-oxa-9-aza-bicyclo[3.3.1]non-7-yl)-amine, less polar
diastereomer, in 32% yield, mp 215.degree. C. (dec.) as the
hydrochloride salt.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 1.74 (m, 4H), 2.685 (bs, 2H),
2.86 (m, 2H), 2.97 (m, 2H), 3.70 (m, 3H), 3.80 (s, 2H), 3.87 (m,
2H), 4.52 (bs, 2H), 6.42 (d, J=8, 1H), 7.06 (d, J=7, 1H), 7.2-7.4
(m, 7H), 7.47 (t, J=8, 1H), 7.86 (m, 2H). .sup.13 C-NMR
(CDCl.sub.3, .delta.): 31.3, 36.4, 47.8, 50.8, 52.5, 55.9, 71.4,
106.9, 110.75, 127.0, 128.3, 128.5, 129.0, 137.8, 138.4, 139.2,
140.6, 156.1, 158.3. MS (%): 429 (parent+1, 12), 216 (67), 91
(100). Anal. Calc'd. for C.sub.27 H.sub.32 N.sub.4 O.3HCl.H.sub.2
O: C, 58.33, H, 6.71, N 10.08. Found: C, 58.30, H, 6.78, N
9.92.
EXAMPLE 103
2-(4-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-piperazin-1-yl)-1-phenyl-e
thanol
Prepared from Example 16, using sodium borohydride in methanol at
room temperature for 2 h in 98.5% yield, mp 235.degree. C. (dec.)
as the hydrochloride salt. .sup.1 H-NMR (CDCl.sub.3, .delta.): 2.51
(m, 6H), 2.63 (m, 4H), 2.82 (m, 4H), 4.10 (bs, 1H), 4.54 (bs, 2H),
4.74 (m, 1H), 6.39 (d, J=8, 1H), 7.05 (d, J=8, 1H), 7.2-7.4 (m,
7H), 7.45 (t, J=8, 1H), 7.84 (m, 2H). .sup.13 C-NMR (CDCl.sub.3,
.delta.): 33.4, 53.3, 60.3, 66.2, 68.8, 106.9, 110.7, 125.9, 126.9,
127.5, 128.4, 128.9, 137.7, 138.3, 140.8, 142.2, 156.0, 158.3. MS
(%): 403 (parent+1, 100), 295 (54), 219 (41), 197 (76), 113 (35),
97 (89). Anal. Calc'd. for C.sub.25 H.sub.30 N.sub.4
O.3HCl.1/2H.sub.2 O: C, 57.64, H, 6.58, N, 10.76. Found: C, 57.66,
H, 6.45, N 10.77.
EXAMPLE 104
{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-(3-oxa-9-aza-bicyclo[3.3.
1]non-7-yl)-amine
Prepared from Example 101, using ammonium formate and
palladium-on-carbon in refluxing ethanol in 81% yield, mp
100.degree. C. (dec.) as the hydrochloride salt.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 1.69 (m, 1H), 2.06 (m, 1H),
2.6-3.0 (m, 5H), 3.5-3.9 (m, 4H), 4.64 (bs, 2H), 6.35 (d, J=8, 1H),
7.00 (d, J=8, 1H), 7.23 (m, 2H), 7.40 (t, J=8, 1H), 7.81 (m, 2H).
MS (%): 339 (parent+1, 100), 254 (35), 199 (45), 159 (38). HRMS
Calc'd. for C.sub.20 H.sub.27 N.sub.4 O (parent+1): 339.2184.
Found: 339.2164.
EXAMPLE 105
6-(4-{2-[4-(2-Amino-2-phenyl-ethyl)-piperazin-1-yl]-ethyl}-phenyl)-pyridin-
2-ylamine
Prepared from Example 16, by forming the oxime methyl ether with
O-methyl hydroxylamine hydrochloride in refluxing methanol followed
by reduction using borane methyl sulfide in refluxing
tetrahydrofuran in 54% yield, as the hydrochloride salt.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 2.2-2.9 (m, 14H), 4.12 (m, 1H),
4.52 (bs, 2H), 6.39 (d, J=8, 1H), 7.03 (d, J=7, 1H), 7.2-7.4 (m,
7H), 7.45 (t, J=7, 1H), 7.81 (m, 2H). MS (%): 402 (parent+1, 6),
149 (100), 119 (47). HRMS Calc'd. for C.sub.25 H.sub.32 N.sub.5
(parent+1): 402.2658. Found: 402.2657.
EXAMPLE 106
9-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-3-oxa-9-aza-bicyclo[3.3.
1]non-7-ylamine
Prepared as in Example 1, using
N-t-butoxycarbonyl-3-oxa-9-aza-bicyclo[3.3.1]non-7-ylamine in 9.5%
yield, followed by removal of the t-butoxycarbonyl group using
trifluoroacetic acid in methylene chloride at room temperature in
88% yield, as the hydrochloride salt.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 1.36 (m, 2H), 2.36 (m, 2H),
2.46 (bs, 2H), 2.70 (m, 4H), 2.81 (m, 2H), 3.14 (m, 1H), 3.68 (m,
2H), 3.87 (m, 2H), 4.51 (bs, 2H), 6.40 (d, J=8, 1H), 7.04 (d, J=7,
1H), 7.23 (m, 2H), 7.45 (t, J=8, 1H), 7.82 (m, 2H). .sup.13 C-NMR
(CDCl.sub.3, .delta.): 31.5, 34.5, 42.1, 51.4, 53.9, 69.8, 106.9,
110.7, 126.7, 129.0, 137.6, 138.3, 140.9, 156.0, 158.0. FAB MS (%):
339 (parent+1, 46), 322 (51), 197 (65), 149 (74), 119 (100), 103
(77), 98 (74). Anal. Calc'd. for C.sub.20 H.sub.26 N.sub.4
O.3HCl.H.sub.2 O.3/2(C.sub.4 H.sub.10 O): C, 54.12, H, 8.04, N,
9.71, Found: C, 54.31, H, 7.63, N, 9.37. HRMS Calc'd. for C.sub.20
H.sub.27 N.sub.4 O (parent+1): 339.2184. Found: 339.2155.
EXAMPLE 107
{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-3-oxa-9-aza-bicyclo[3.3.
1]non-7-yl)-amine
Prepared as in Example 102, using ammonium formate and
palladium-on-carbon in refluxing ethanol in 87% yield, mp
170.degree. C. (dec.) as the hydrochloride salt.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 1.36 (m, 2H), 2.09 (m, 2H),
2.79 (m, 2H), 2.91 (m, 4H), 3.7-3.9 (m, 5H), 4.56 (bs, 2H), 13.36
(d, J=8, 1H), 7.01 (d, J=7, 1H), 7.23 (m, 2H), 7.42 (t, J=8, 1H),
7.81 (m, 2H). .sup.13 C-NMR (CDCl.sub.3, .delta.): 36.4, 39.2,
47.7, 48.9, 50.5, 71.7, 106.9, 110.6, 126.9, 128.9, 137.7, 138.3,
140.6, 155.9, 158.3. MS (%): 339 (parent+1, 6), 167 (21), 149
(100), 129 (12), 113 (31). Anal. Calc'd. for C.sub.20 H.sub.26
N.sub.4 O.3HCl.3/2H.sub.2 O: C, 51.62, H, 7.29, N, 10.94. Found: C,
51.65, H, 7.24, N, 10.95.
EXAMPLE 108
6-{4-[2-(4-Amino-2,6-dimethyl-piperidin-1-yl)-ethyl]-phenyl}-pyridin-2-ylam
ine (cis diastereomer)
A. N-Benzyl-2,6-dimethylpiperidin-4-one:
To a 500 mL round-bottomed flask equipped with condenser and
N.sub.2 inlet were added 40 g (0.28 mol) 1,3-acetonedicarboxylic
acid, 24.8 g (0.64 mol) acetaldehyde, and 60 mL water. To the
resulting mixture was added slowly, 30 mL (0.28 mol) benzylamine
over 30 minutes, the pH was adjusted to 4-5, and the reaction
stirred overnight at room temperature. After filtration, the
reaction pH was adjusted to 10 with 6 N sodium hydroxide, and
extracted with ethyl acetate. The organic layer was washed with
brine, dried, and evaporated, and the resulting residue
chromatographed on silica gel using hexane/ethyl acetate as eluant
to afford both isomers:
Trans isomer: 10.1 g (16.5%) oil. .sup.1 H-NMR (CDCI.sub.3,
.delta.): 1.07 (d,J=7, 6H), 2.17 (m, 2H), 2.47 (m, 2H), 3.25 (m,
2H), 3.75 (Ab.sub.q, J=14, Dn=110, 2H), 7.23 (m, 1H), 7.29 (m, 2H),
7.37 (m, 2H). .sup.13 C-NMR (CDCI.sub.3, .delta.): 17.4, 47.4,
51.3, 51.8, 126.9, 128.2, 128.3, 140.2, carbonyl carbon not visible
in this scan. MS (%): 218 (parent+1, 100). Cis isomer: 3.31 g
(5.4%) oil. .sup.1 H-NMR (CDCl.sub.3, .delta.): 1.13 (d, J=6, 6H),
2.32 (m, 4H), 3.10 (m, 2H), 3.83 (s, 2H), 7.21 (m, 1H), 7.30 (m,
2H), 7.39 (m, 2H). .sup.13 C-NMR (CDCI.sub.3, .delta.): 21.5, 47.1,
50.0, 57.3, 126.5, 127.6, 128.2, 141.0, carbonyl carbon not visible
in this scan. MS (%): 218 (parent+1, 100).
B. N-Benzyl-2,6-dimethylpiperidin-4-one methoxime (cis isomer):
To a 100 mL round-bottomed flask equipped with condenser and
N.sub.2 inlet were added 3.31 g (15.2 mmol)
N-benzyl-2,6-dimethylpiperidin-4-one, cis isomer, 2.1 g (24.3 mmol)
methoxime hydrochloride, 3.4 mL (24.3 mmol) triethylamine, and 50
mL methanol. The reaction was refluxed 24 h, cooled, and
evaporated. The residue was taken up in water/ethyl acetate, and
the organic layer seperated, washed with brine, dried, and
evaporated. The residue was chromatographed on silica gel using
hexane/ethyl acetate to afford 1.5 g (40%) of an oil.
.sub.1 H-NMR (CDCI.sub.3, .delta.): 1.10 (m, 6H), 1.92 (m, 1H),
2.11 (m, 1H), 2.29 (m, 1H), 2.80 (m, 1H), 2.87 (m, 1H), 2.92 (m,
1H), 3.78 (s, 2H), 3.81 (s, 3H), 7.19 (m, 1H), 7.28 (m, 2H), 7.36
(m, 2H). .sup.13 C-NMR (CDCI.sub.3, .delta.): 16.5, 16.6, 31.6,
37.8, 49.65, 50.6, 52.3, 61.1, 126.7, 128.2, 140.6, 157.3. APCI MS
(%): 247 (parent+1, 100),
C. N-Benzyl-2,6-dimethylpiperidin-4-amine (cis isomer):
To a 100 mL round-bottomed flask equipped with condenser and
N.sub.2 inlet were added 1.5 g (6.1 mmol)
N-benzyl-2,6-dimethylpiperidin-4-one methoxime (cis isomer), 60 mL
dry tetrahydrofuran, and 15 mL (30 mmol) of a 2.0 M solution of
borane methyl sulfide in tetrahydrofuran. The reaction was refluxed
24 h, cooled, and the solvent evaporated. The residue was treated
with 60 mL ethanol, 1.9 g (18.3 mmol) sodium carbonate, and 1.5 g
cesium fluoride. The reaction was refluxed 24 h, cooled, and
evaporated. The residue was taken up in water/ethyl acetate, and
the organic layer washed with brine, dried over sodium sulfate, and
evaporated to afford 1.5 g (100%) of an oil.
.sup.1 H-NMR (CDCI.sub.3, .delta.): 1.07 (d,J=6, 6H), 1.41 (m, 2H),
1.70 (m, 2H), 2.56 (m, 2H), 2.66 (m, 1H), 3.77 (s, 2H), 7.17 (m,
1H), 7.25 (m, 2H), 7.34 (m, 2H). .sup.13 H-NMR (CDCI.sub.3,
.delta.): 11.3, 21.7, 40.8, 44.4, 45.1, 48.5, 50.4, 52.5, 126.4,
128.1, 128.2, 141.2. MS (%): 219 (parent+1,100).
D. N-Benzyl-2,6-dimethylpiperidin-4-amine t-butylcarbamate (cis
isomer):
To a 100 mL round=bottomed flask equipped with condenser and
N.sub.2 inlet were added 1.3 g (6.0 mmol)
N-benzyl-2,6-dimethylpiperidin-4-amine (cis isomer), 1.3 g (6.0
mmol) di-t-butyl-dicarbonate, 1.2 mL (8.9 mmol) triethylamine, and
50 mL methylene chloride. The reaction was stirred at room
temperature overnight, then washed with aqueous citric acid, water,
and brine, dried over sodium sulfate, and evaporated. The residue
was chromatographed on silica gel using methylene chloride/ethyl
acetate as eluant to afford 1.6 g (84%) of an oil.
.sup.1 H-NMR (CDCI.sub.3, .delta.): 1.05 (d, J=6, 6H), 1.13 (q,
J=12, 2H), 1.42 (s, 9H), 1.87 (m, 2H), 2.59 (m, 2H), 3.5 (bs, 1H),
3.76 (s, 2H), 4.3 (m, 1H), 7.18 (m, 1H), 7.24 (m, 2H), 7.33 (m,
2H). .sup.13 C-NMR (CDCI.sub.3, .delta.): 10.8, 21.6, 28.5, 37.6,
41.7, 44.2, 50.2, 52.7, 79.0, 126.5, 128.1, 128.2, 141.0, 155.3.
APCI MS (%): 319 (parent+1, 100),
E. 2,6-Dimethylpiperidin-4-amine t-butylcarbamate (cis isomer):
To a 100 mL round-bottomed flask equipped with condenser and
N.sub.2 inlet were added 1.6 g (5.0 mmol)
N-benzyl-2,6-dimethylpiperidin-4-amine t-butylcarbamate (cis
isomer), 2.5 g ammonium formate, 250 mg 10% palladium-on-carbon,
and 40 mL ethanol. The reaction was refluxed 2 h, cooled, and
filtered through Celite with ethanol and methylene chloride. The
filtrate was evaporated, the residue was taken up in ethyl
acetate/water, the organic layer separated, washed with brine,
dried over sodium sulfate, and evaporated to give a low-melting,
white solid, 1.09 g (95.5%).
.sup.1 H-NMR (CDCI.sub.3, .delta.): 0.81 (q, J=11, 2H), 1.06 (d,
J=6, 6H), 1.41 (s, 9H), 1.91 (m, 2H), 2.72 (m, 2H), 3.5 (bs, 1H),
4.4 (m, 1H). .sup.13 C-NMR (CDCI.sub.3, .delta.): 19.0, 22.8, 28.3,
37.5, 42.3, 43.7, 44.0, 47.6, 78.9. MS (%): 229 (parent+1, 62), 173
(100).
F2-(2,5-Dimethylpyrrolyl)-6-((4-(4-t-butylcarboxamido-2,6-dimethylpiperidin
-1-yl -carboxamido)methyl)phenyl))-pyridine:
To a 100 mL round-bottomed flask equipped with N.sub.2 inlet were
added 1.3 g (4.4 mmol)
2-(2,5-dimethylpyrrolyl)-6-((4-(carboxymethyl)phenyl))-pyridine,
1.0 g (4.4 mmol) 2,6-dimethylpiperidin-4-amine t -butylcarbamate
(cis isomer), 1.7 g (8.8 mmol) N-ethyl-N-3-dimethylaminopropyl
-carbodiimide, 2.7 g (22 mmol) 4dimethylaminopyridin, and 25 mL
dimethylformamide. The reaction was stirred at room temperature for
24 h, taken up in ethyl acetate/water, and the organic layer
seperated, washed with brine, dried over sodium sulfate, and
evaporated. The residue was chromatographed on silica gel using
hexane/ethyl acetate as eluant to afford 1.8 g (79%) of a foam.
.sup.1 H-NMR (CDCI.sub.3, .delta.): 1.89 (m, 8H), 1.35 (s, 9H), 2.1
(m, 2H), 2.16 (s, 6H), 3.4 (bs, 1H), 3.72 (s, 2H), 4.8 (m, 1H),
5.86 (s, 2H), 7.05 (d,J=8, 1H), 7.28 (m, 2H), 7.68 (d, J=8, 1H),
7.79 (t, J=8, 1H), 7.98 (m, 2H). .sup.13 C-NMR (CDCI.sub.3,
.delta.): 13.4, 28.3, 35.6, 41.3, 44.1, 47.0, 60.2, 79.1, 106.9,
118.1, 119.65, 127.1, 128.4, 128.9, 136.7, 138.5, 151.5, 155.0,
156.4, 169.7. APCI MS (%): 517 (parent+1, 65), 461 (100), 417
(32).
G.
2-(2,5-Dimethylpyrrolyl)-6-((4-(4-amino-2,6-dimethylpiperidin-1-yl
-carboxamido)methyl)phenyl))-pyridine:
To a 100 mL round-bottomed flask equipped with N.sub.2 inlet were
added 1.0 g (1.94 mmol) 2-(2,5-dimethylpyrrolyl)-6-((4-(6-t
-butylcarboxamido-2,6-dimethylpiperidin-4-yl-carboxamido)methyl)phenyl))-p
yridine, 100 mL ethyl acetate, and the solution cooled to 0.degree.
C. and saturated with HCI. The reaction was stirred 15 min at room
temperature, evaporated, and the residue taken up in 1 N sodium
hydroxide solution and extracted with methylene chloride. The
organic layer was washed with brine, dried over sodium sulfate, and
evaporated to give 770 mg (95.5%) of a foam. .sup.1 H-NMR
(CDCI.sub.3, .delta.): 1.18 (m, 2H), 1.22 (d, J=7, 6H), 1.97 (m,
2H), 2.15 (s, 6H), 2.68 (m, 1H), 3.72 (s, 2H), 4.3 (bs, 2H), 5.86
(s, 2H), 7.06 (d, J=8, 1H), 7.27 (m, 2H), 7.66 (d, J=8, 1H), 7.79
(t, J=8, 1H), 7.97 (m, 2H). .sup.13 C-NMR (CDCI.sub.3, .delta.):
13.4, 24.3, 39.0, 41.6, 44.7, 47.1, 60.2, 106.9, 118.1, 119.7,
127.1, 128.45, 128.9, 136.7, 136.9, 138.5, 151.5, 156.3, 169.7. MS
(%): 417 (parent+1, 100).
H.
2-(2,5-Dimethylpyrrolyl)-6-{4-[2-(4-amino-2,6-dimethyl-piperidin-1-yl)-eth
yl]-phenyl}-pyridine (cis diastereomer):
To a 100 mL three-necked round-bottomed flask equipped with
condenser, septum and N2 inlet were added 640 mg (4.8 mmol)
aluminum chloride, 20 mL dry tetrahydrofuran, and after cooling to
0.degree. C., 11.2 mL (11.2 mmol) of a 1.0 M solution of lithium
aluminum hydride in tetrahydrofuran. After stirring at 0.degree. C.
for 1 h, the reaction was cooled to .78.degree. C., and a solution
of 670 mg (1.6 mmol)
2-(2,5-dimethylpyrrolyl)-6-((4-(4-amino-2,6-dimethylpiperidin-1-yl
-carboxamido)methyl)phenyl))-pyridine in 10 mL dry tetrahydrofuran
added, and stirring continued at .78.degree. C. for 1 h. The
reaction was then warmed to room temperature and stirred overnight.
The reaction was carefully quenched with dilute hydrochloric acid,
the pH adjusted to 10 with 6 N sodium hydroxide solution, and
extracted with ethyl acetate. The organic layer was washed with
brine, dried over sodium sulfate, and evaporated. The residue was
chromatographed on silica gel using methanol/methylene chloride as
eluant to give 423 mg (66%) of an oil. .sup.1 H-NMR (CDCI.sub.3,
.delta.): 1.17 (m, 2H), 1.22 (d, J=6, 6H), 1.81 (m, 2H), 1.95 (bs,
2H), 2.19 (s, 6H), 2.70 (m, 5H), 2.99 (m, 2H), 5.90 (s, 2H), 7.08
(d, J=8, 1H), 7.22 (m, 2H), 7.68 (d, J=8, 1H), 7.81 (t, J=8, 1H),
7.97 (m, 2H). .sup.13 C-NMR (CDCI.sub.3, .delta.): 13.4, 21.0,
45.1, 48.1, 48.6, 49.4, 49.9, 53.4, 106.9, 117.9, 119.5, 127.0,
158.5, 158.9, 136.1, 138.5, 142.2, 151.5, 156.6. MS (%): 403
(parent+1, 100).
I.
6-{4-[2-(4-Amino-2,6-dimethyl-piperidin-1-yl)-ethyl]-phenyl}-pyridin-2-yla
mine (cis diastereomer):
The deblocking was carried out using hydroxylamine hydrochloride as
described in Example 124 F to afford the product as an oil in 100%
yield, which was converted to the hydrochloride salt as an
amorphous solid. .sup.1 H-NMR (CDCI.sub.3, .delta.): 1.06 (m, 2H),
1.18 (d, J=6, 6H), 1.75 (m, 2H), 2.63 (m, 5H), 2.95 (m, 2H), 4.58
(bs, 2H), 6.35 (d, J=8, 1H), 6.99 (d, J=8, 1H), 7.15 (m, 2H), 7.40
(t, J=8, 1H), 7.79 (m, 2H). .sup.13 C-NMR (CDCI.sub.3, .delta.):
21.0, 45.3, 48.1, 48.6, 49.4, 53.4, 106.8, 110.5, 126.8, 128.6,
137.4, 138.2, 141.1, 155.8, 158.2. FAB MS (%): 325 (parent+1, 18),
149 (69), 119 (100). HRMS Calc'd. for C.sub.20 H.sub.29 N.sub.4
(parent+1): 325.2392. Found: 325.2369.
EXAMPLE 109
6-{4-[2-(4-Methyl-piperazin-1-yl)-ethyl]-phenyl}-pyridin-2-ylamine
Prepared as in Example 1, using N-methylpiperazine in 74% yield, mp
170.degree. C. (dec.) as the hydrochloride salt.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 2.26 (s, 3H), 2.4-2.6 (broad
multiplet, 8H), 2.60 (m, 2H), 2.80 (m, 2H), 4.56 (bs, 2H), 6.35 (d,
J=8, 1H), 7.00 (d, J=7, 1H), 7.23 (m, 2H), 7.41 (t, J=8, 1H), 7.80
(m, 2H). .sup.13 C-NMR (CDCl.sub.3, .delta.): 33.3, 46.1, 53.1,
55.1, 60.3, 106.8, 110.6, 126.8, 128.9, 137.6, 138.3, 140.8, 156.0,
158.3. FAB MS (%): 297 (parent+1, 100), 197 (28), 113 (73). Anal.
Calc'd. for C.sub.18 H.sub.24 N.sub.4.3HCl.1/2H.sub.2 O: C, 52.12,
H, 6.80, N, 13.51. Found: C, 52.05, H, 7.00, N, 13.07.
EXAMPLE 110
6-{4-[2-(4-Benzenesulfonyl-piperazin-1-yl)-ethyl]-phenyl}-pyridin-2-ylamine
Prepared as in Example 1, using N-benzenesulfonylpiperazine in 93%
yield, as the hydrochloride salt.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 2.60 (m, 6H), 2.74 (m, 2H),
3.04 (m, 4H), 4.64 (bs, 2H), 6.44 (d, J=8, 1H), 7.03 (d, J=t, 1H),
7.20 (m, 2H), 7.48 (t, J=8, 1H), 7.52 (m, 3H), 7.73 (m, 2H), 7.81
(m, 2H). .sup.13 C-NMR (CDCl.sub.3, .delta.): 33.0, 45.8, 51.9,
59.4, 106.9, 110.4, 126.7, 127.6, 128.6, 128.8, 132.6, 135.0,
133.4, 140.0, 156.0, 158.0. FAB MS (%): 423 (parent+1, 25), 167
(25), 149 (100), 113 (22). Anal. Calc'd. for C23H.sub.26 N.sub.4
O.sub.2 S.2HCl.5/4H.sub.2 O: C, 53.33, H, 5.94, N, 10.82. Found: C,
53.33, H, 5.92, N, 10.45.
EXAMPLE 111
6-{4-[2-(4-Methanesulfonyl-piperazin-1-yl)-ethyl]-phenyl}-pyridin-2-ylamine
Prepared as in Example 1, using N-methanesulfonylpiperazine in 15%
yield, as the hydrochloride salt.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 2.61 (m, 4H), 2.65 (m, 2H),
2.76 (s, 3H), 2.80 (m, 2H), 3.23 (m, 4H), 4.49 (bs, 2H), 6.42 (d,
J=8, 1H), 7.04 (d, J=7, 1H), 7.23 (m, 2H), 7.46 (t, J=8, 1H), 7.83
(m, 2H). .sup.13 C-NMR (CDCl.sub.3, .delta.): 33.1, 33.9, 45.8,
52.2, 59.6, 106.9, 110.6, 126.8, 128.8, 137.6, 138.3, 140.3, 155.8,
158.1. MS (%): 361 (parent+1, 17), 149 (100), 135 (54), 119 (89),
103 (48). Anal. Calc'd. for C.sub.18 H.sub.24 N.sub.4 O.sub.2
S.2HCl: C, 49.88, H, 6.05, N, 12.93. Found: C, 50.11, H, 6.08, N,
11.69.
EXAMPLE 112
6-{4-[2-(2,6-Dimethyl-piperazin-1-yl)-ethyl]-phenyl}-pyridin-2-ylamine:
Refer to Scheme 2
A. 2-(2,5-Dimethylpyrrolyl)-6-(4-formylphenyl)-pyridine:
To a 1 L round-bottomed flask equipped with condenser and N.sub.2
inlet were added 20.0 g (79.6 mmol)
6-bromo-2-(2,5-dimethylpyrrolyl)-pyridine, 11.9 g (79.6 mmol)
4-formylphenyl boronic acid, 33.8 g (300 mmol) sodium carbonate, 1
g (0.8 mmol) tetrakis-triphenylphosphine palladium, 370 mL ethanol,
and 40 mL water. The mixture was refluxed 16 h, cooled, poured into
water, and extracted into ethyl acetate. The organic layer was
washed with brine, dried over sodium sulfate, and evaporated. The
residue was chromatographed on silica gel using hexane/ethyl
acetate as eluant to afford 21.0 g (95.5%) of a light yellow,
solid, mp 106-108.degree. C.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 2.21 (s, 6H), 5.94 (s, 2H),
7.22 (d, J=8, 1H), 7.82 (d, J=8, 1H), 7.93 (t, J=8, 1H), 7.98 (m,
2H), 8.22 (m, 2H), 10.07 (s, 1H).
.sup.13 C-NMR (CDCl.sub.3, .delta.): 13.4, 107.2, 119.0, 120.9,
127.4, 128.6, 130.1, 136.6, 138.8, 155.2, 191.9.
APCI MS (%): 277 (parent+1, 100).
B. 2-(2,5-Dimethylpyrrolyl)-6-(4-(cyanomethyl)phenyl)-pyridine:
To a 2 L round-bottomed flask equipped with condenser and N.sub.2
inlet were added 17.1 g (152 mmol) potassium t-butoxide and 250 mL
dry 1,2-dimethoxyethane (DME). The reaction was cooled to
-60.degree. C., and a solution of 16.2 g (83 mmol)
tosylmethylisocyanide in 250 mL DME added dropwise over 5 minutes.
After stirring for 5 minutes, a solution of 21.0 g (76 mmol)
2-(2,5-dimethylpyrrolyl)-6-(4-formylphenyl)-pyridine in 500 mL DME
was added dropwise over 10 minutes, and stirring continued at
-60.degree. C. for 1 h. Then 250 mL methanol was added, and the
reaction warmed to room temperature, then refluxed 20 minutes. The
reaction was cooled, evaporated, taken up in wIater and 8 mL acetic
acid, and extracted with methylene chloride. The organic layer was
washed with brine, dried over sodium sulfate, and evaporated. The
residue was chromatographed with hexane/methylene chloride on
silica gel to give 16.8 g (77%) of a low-melting solid.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 2.21 (s, 6H), 3.80 (s, 2H),
5.93 (s, 2H), 7.16 (d, J=8, 1H), 7.42 (m, 2H), 7.74 (d, J=8, 1H),
7.89 (t, J=8, 1H), 8.08 (m, 2H).
APCI MS (%): 287 (parent+1, 100).
C.
2-(2,5-Dimethylpyrrolyl)-6-(4-(carboxymethyl)phenyl)-pyridine:
To a 2 L round-bottomed flask equipped with condenser and N.sub.2
inlet were added 16.8 g (58.5 mmol)
2-(2,5-dimethylpyrrolyl)-6-(4-(cyanomethyl)phenyl)-pyridine and 500
mL ethanol. The reaction was heated to reflux, and 1400 mL of a 10%
aqueous sodium hydroxide solution added dropwise over 2 h. The
reaction was refluxed an additional 2 h, cooled, and evaporated to
a small volume, then the pH adjusted to 1 with concentrated
hydrochloric acid (ice-cooling), and extracted into ethyl acetate.
The organic layer was washed with biine, dried over sodium sulfate,
and evaporated to a light yellow, low-melting solid, 16.9 g
(94%).
.sup.1 H-NMR (CDCl.sub.3, .delta.): 2.20 (s, 6H), 3.69 (s, 2H),
5.92 (s, 2H), 7.13 (d, J=8, 1H), 7.37 (m, 2H), 7.72 (d, J=8, 1H),
7.86 (t, J=8, 1H), 8.03 (m, 2H). .sup.13 C-NMR (CDCl.sub.3,
.delta.): 13.4, 40.7, 106.9, 118.2, 119.9, 127.1, 128.6, 129.8,
134.5, 137.4, 138.6, 151.6, 156.3, 177.4. APCI MS (%): 307
(parent+1, 100).
D.
2-(2,5-Dimethylpyrrolyl)-6-(4-((2,6-dimethyl-4-t-butoxycarbonyl)piperazin-
1-yl)methyl)phenyl)-pyridine:
To a 100 mL round-bottomed flask equipped with N.sub.2 inlet were
added 500 mg (1.6 mmol)
2-(2,5-dimethylpyrrolyl)-6-(4-(carboxymethyl)phenyl)-pyridine, 350
mg (1.6 mmol) 2,6-dimethyl-4-t-butoxycarbonyl-piperazine, 626 mg
(3.2 mmol) N-ethyl-N-3-dimethylaminopropyl-carbodiimide, 996 mg
(8.1 mmol) 4-dimethylamino-pyridine, and 10 mL dry
dimethylformamide. The reaction was stirred at room temperature for
16 h, poured into water, and extracted into ethyl acetate. The
organic layer was washed with water and brine, dried over sodium
sulfate, and evaporated. The residue was chromatographed on solica
gel using methanol/methylene chloride as eluant to afford 817 mg
(100%) of a foam.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 1.23 (d, J=7, 6H), 1.44 (s,
9H), 2.19 (s, 6H), 2.8 (m, 4H), 3.76 (m, 2H), 4.0 (m, 2H), 5.91 (s,
2H), 7.12 (d, J=8, 1H), 7.33 (m, 2H), 7.72 (d, J=8, 1H), 7.85 (t,
J=8, 1H), 8.01 (m, 2H). .sup.13 C-NMR (CDCl.sub.3, .delta.): 13.4,
19.8, 21.0, 28.2, 40.8, 44.8, 46.9, 48.1, 48.9, 79.9, 106.9, 118.1,
119.7, 127.2, 128.5, 128.9, 136.4, 136.9, 138.5, 151.6, 155.2,
156.3, 169.8. APCI MS (%): 503 (parent+1, 40), 447 (100), 403
(55).
E. 6-(4-((2,6-Dimethyl)piperazin-1-yl)methyl)phenyl)-pyridin-2-yl
amine:
2-(2,5-Dimethylpyrrolyl)-6-(4-((2,6-dimethyl-4-t-butoxycarbonyl)piperazin-1
-yl)methyl)phenyl)-pyridine was deblocked first with hydroxylamine
hydrochloride as described in Example 1F, then with trifluoroacetic
acid in methylene chloride as described in Example 2 to afford 455
mg (88% overall) of a foam.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 1.28 (d, J=7, 6H), 2.8 (m, 4H),
3.74 (s, 2H), 4.55 (m, 2H), 6.43 (d, J=8, 1H), 7.05 (d, J=8, 1H),
7.30 (m, 2H), 7.47 (t, J=8, 1H), 7.86 (m, 2H). .sup.13 C-NMR
(CDCl.sub.3, .delta.): 40.5, 44.0, 48.2, 50.1, 107.2, 110.4, 126.9,
128.7, 135.7, 138.0, 138.3, 155.3, 158.4, 170.0. IR (KBr,
cm..sup.-1): 1620 (C.dbd.O). APCI MS (%): 325 (parent+1, 100).
F.
6-{4-[2-(2,6-Dimethyl-piperazin-1-yl)ethyl]-phenyl}-pyridin-2-ylamine:
6-(4-((2,6-Dimethyl)piperazin-1-yl)methyl)phenyl)-pyridin-2-yl
amine was reduced with borane methyl sulfide as described in
Example 124B to give an 8% yield of a hygroscopic solid as the
hydrochiloride salt.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 1.13 (d, 6H), 2.53 (m, 2H),
2.68 (m, 4H), 2.90 (m, 2H), 3.00 (m, 2H), 4.49 (bs, 2H), 6.42 (d,
J=8, 1H), 7.04 (d, J=7, 1H), 7.19 (m, 2H), 7.46 (t, J=8, 1H), 7.82
(m, 2H). .sup.13 C-NMR (CDCl.sub.3, .delta.): 17.6, 28.7, 49.8,
53.6, 54.2, 106.8, 110.6, 126.9, 128.6, 137.5, 138.3, 141.1, 155.9,
158.1. MS (%): 311 (parent+1, 14), 167 (23), 149 (100). HRMS
Calc'd. for C.sub.19 H.sub.27 N.sub.4 : 311.2236. Found:
311.2236.
EXAMPLE 113
6-{4-[2-(2,6-Dimethyl-4-methylamino-piperidin-1-yl)-ethyl]-phenyl}-pyridin-
2-ylamine
Prepared as in Example 112, using
4-t-butoxycarbonylamino-2,6-dimethylpiperidine coupling with
2-(2,5-dimethylpyrrolyl)-6-(4-(carboxymethyl)phenyl)-pyridin in 75%
yield, followed by reduction with borane methyl sulfide in
refluxing tetrahydrofuran in 17% yield, followed by deprotection
using hydroxylamine hydrochloride in refluxing ethanol in 85%
yield, as a hygroscopic solid as the hydrochloride salt.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 1.06 (m, 6H), 1.23 (m, 2H),
1.81 (m, 2H), 2.43 (s, 3H), 2.53 (m, 1H), 2.7-2.9 (m, 6H), 4.51
(bs, 2H), 6.41 (d, J=8, 1H), 7.03 (d, J=7, 1H), 7.24 (m, 2H), 7.45
(t, J=8, 1H), 7.82 (m, 2H). .sup.13 C-NMR (CDCl.sub.3, .delta.):
11.4, 21.3, 32.4, 35.4, 36.6, 40.1, 48.7, 50.8, 51.1, 52.0, 106.9,
110.7, 126.8, 129.0, 137.5, 138.3, 141.3, 156.1, 158.2. APCI MS
(%): 339 (parent+1, 100). Anal. Calc'd. for C.sub.21 H.sub.30
N.sub.4.3HCl.1/2CH.sub.2 Cl.sub.2.9/4(C.sub.4 H.sub.10 O): C,
55.75, H, 8.67, N, 8.53. Found: C, 55.66, H, 8.21, N, 8.02.
EXAMPLE 114
6-{4-[2-(4-cyclohexyl-piperazin-1-yl)-ethyl]-phenyl}-pyridin-2-ylamine
Prepared as in Example 112, using N-cyclohexylpiperazine coupling
with 2-(2,5-dimethylpyrrolyl)-6-(4-(carboxymethyl)phenyl)-pyridine
in 100% yield followed by reduction using borane methyl sulfide in
refluxing tetrahydrofuran in 97% yield, then deprotection using
hydroxylamine hydrochloride in refluxing ethanol in 98% yield, as
the hydrochloride salt.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 1.09 (m, 6H), 1.75 (m, 2H),
1.88 (m, 2H), 2.24 (m, 1H), 2.59 (m, 10H), 2.83 (m, 2H), 4.53 (bs,
2H), 6.38 (d, J=8, 1H), 7.02 (d, J=8, 1H), 7.22 (m, 2H), 7.43 (t,
J=8, 1H), 7.81 (m, 2H). .sup.13 C-NMR (CDCl.sub.3, .delta.): 25.5,
25.9, 28.5, 33.0, 48.5, 53.2, 60.0, 63.1, 106.5, 110.3, 126.4,
128.5, 137.2, 137.9, 140.5, 155.6, 157.8. APCI MS (%): 365
(parent+1, 100). Anal. Calc'd. for C.sub.23 H.sub.32
N.sub.4.3HCl.1/4H.sub.2 O.1/4(C.sub.4 H.sub.10 O).1/4CH.sub.2
Cl.sub.2 : C, 56.21, H, 7.49, N, 10.81. Found: C, 56.12, H, 7.83,
N, 10.44.
EXAMPLE 115
6-{4-[2-(Adamantan-1-ylamino)-ethyl]-phenyl}-pyridin-2-ylamine
Preparedas in Example 112, using 1-aminoadamantane for the coupling
with 2-(2,5-dimethylpyrrolyl)-6-(4-(carboxymethyl)phenyl)-pyridine
followed by deblocking with hydroxylamine hydrochloride and borane
methyl sulfide reduction in 89.5% yield, mp 200-220.degree. C.
(dec.) as the hydrochloride salt.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 1.58 (bs, 12H), 2.02 (bs, 3H),
2.80 (m, 2H), 2.85 (m, 2H), 4.54 (bs, 2H), 6.40 (d, J=8, 1H), 7.03
(d, J=7, 1H), 7.25 (m, 2H), 7.45 (t, J=8, 1H), 7.83 (m, 2H).
.sup.13 C-NMR (CDCl.sub.3, .delta.): 29.6, 36.7, 36.8, 41.7, 42.6,
50.5, 106.9, 110.7, 126.9, 128.9, 137.7, 138.3, 140.7, 156.0,
158.3. FAB MS (%): 348 (parent+1, 44), 135 (100). Anal. Calc'd. for
C.sub.23 H.sub.29 N.sub.3.2HCl.3/2H.sub.2 O.1/2(C.sub.4 H.sub.10
O): C, 61.98, H, 8.11, N, 8.67. Found: C, 61.95, H, 7.90, N,
8.69.
EXAMPLE 116
6-{4-[2-(Adamantan-2-ylamino)-ethyl]-phenyl}-pyridin-2-ylamine
Prepared as in Example 112, using 2-aminoadamantane for the
coupling with
2-(2,5-dimethylpyrrolyl)-6-(4-(carboxymethyl)phenyl)-pyridine
followed by deblocking with hydroxylamine hydrochloride and borane
methyl sulfide reduction in 98% yield, mp 215-230.degree. C. (dec.)
as the hydrochloride salt.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 1.43 (m, 2H), 1.67 (bs, 4H),
1.81 (m, 8H), 2.72 (bs, 1H), 2.85 (m, 4H), 4.53 (bs, 2H), 6.40 (d,
J=8, 1H), 7.04 (d, J=7, 1H), 7.26 (m, 2H), 7.45 (t, J=8, 1H), 7.83
(m, 2H). .sup.13 C-NMR (CDCl.sub.3, .delta.): 27.5, 27.8, 31.3,
32.0, 37.6, 37.9, 48.1, 106.8, 110.7, 126.8, 128.9, 137.6, 138.3,
141.0, 156.1, 158.2. FAB MS (%): 348 (parent+1, 80), 135 (100).
Anal. Calc'd. for C.sub.23 H.sub.29 N.sub.3.2HCl.7/4H.sub.2
O.3/4(C.sub.4 H.sub.10 O): C, 61.53, H, 8.34, N, 8.28. Found: C,
61.55, H, 8.12, N, 8.01.
EXAMPLE 117
6-{4-[2-(Indan-2-ylamino)-ethyl]-phenyl}-pyridin-2-ylamine
A. 6-(4-(2-Aminoethyl)phenyl-2-(2,5-dimethylpyrrolyl)pyridine:
To a 250 mL round-bottomed flask equipped with condenser and N2
inlet were added 3.04 g (10.59 mmol)
6-(4-(cyanomethyl)phenyl-2-(2,5-dimethylpyrrolyl)pyridine, 100 mL
dry tetrahydrofuran, and 53 mL (53 mmol) of a 1.0 M solution of
lithium aluminum hydride in tetrahydrofuran. The reaction was
refluxed 40 h, with 20 mL lithium aluminum hydride reagent solution
added after 24 h, cooled, and quenched carefully with water. The
mixture was taken up in 0.5 N aqueous sodium hydroxide solution and
ethyl acetate, and the organic layer was washed with water, then
extracted with hydrochloric acid. The aqueous layer was washed with
water, then adjusted to pH 10 with aqueous sodium hydroxide
solution and extracted with ethyl acetate. The organic layer was
washed with brine, dried over sodium sulfate, and evaporated to an
oil, 1.37 g (43%), which was used without further purification.
.sup.1 H-NMR (d, CDCl.sub.3): 1.6 (broad, 2H), 2.20 (s, 6H), 2.80
(m, 2H), 2.99 (m, 2H), 5.91 (s, 2H), 7.10 (d, J=8, 1H), 7.28 (m,
2H), 7.70 (m, 1H), 7.84 (m, 1H), 7.98 (m, 2H). MS (APCI) (%): 292
(100, parent+1).
B. 6-{4-[2-(Indan-2-ylamino)-ethyl]-phenyl}-pyridin-2-ylamine:
Prepared from the above oil by reductive amination with 2-indanone
using sodium cyanoborohydride in methanol at room temperature in
17% yield, followed by deblocking with hydroxylamine hydrochloride
in refluxing ethanol in 82.5% yield, mp 60-70.degree. C. (dec.) as
the hydrochloride salt.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 2.72 (AB pattern, 2H), 2.91
(ddd, J=6.6, 7, 38, 4H), 3.14 (AB pattern, 2H), 3.64 (quintet, J=7,
1H), 4.56 (bs, 2H), 6.40 (dd, J=0.4, 8, 1H), 7.04 (dd, J=0.6, 7,
1H), 7.15 (m, 4H), 7.27 (m, 2H), 7.46 (dt, J=0.4, 8, 1H), 7.85 (m,
2H). .sup.13 C-NMR (CDCl.sub.3, .delta.): 36.1, 39.9, 49.4, 59.5,
107.0, 110.8, 124.7, 126.4, 127,0, 128.9, 137.8, 138.4, 140.4,
141.5, 156.0, 158.3. FAB MS (%): 330 (parent+1, 100), 197 (42),
132, (43), 117 (80). Anal. Calc'd. for C.sub.22 H.sub.23
N.sub.3.2HCl.2H.sub.2 O: C, 60.27, H, 6.67, N, 9.58. Found: C,
60.35, H, 6.48, N, 10.00.
EXAMPLE 118
6-(4-(2-Aminoethyl)phenyl-pyridin-2-ylamine
Prepared by deblocking Example 117A above using hydroxylamine
hydrochloride in refluxing ethanol in 56% yield, mp 73-83.degree.
C. (dec.) as the hydrochlo,ride salt.
.sup.1 H-NMR (DMSO-d.sub.6, .delta.): 2.95 (m, 2H), 3.02 (m, 2H),
4.0 (bs, 4H), 6.96 (d, J=9, 1H), 7.21 (d, J=7, 1H), 7.45 (m, 2H),
7.8-8.0 (m, 3H). .sup.13 C-NMR (DMSO-d.sub.6, .delta.): 25.4, 32.8,
40.4, 67.8, 110.0, 111.8, 127.5, 129.9, 140.3, 143.8, 146,3, 155.3.
FAB MS (%): 214(parent+1, 54), 135 (49), 119 (100), 103 (49). HRMS
Calc'd. for C.sub.13 H.sub.16 N.sub.3 (parent+1): 214.1344. Found:
214.1351.
EXAMPLE 119
6-{4-[2-(Bis-pyridin-3-ylmethyl-amino)-ethyl]-phenyl}-pyridin-2-ylamine
Prepared from Example 117A by reductive amination with
pyridine-3-carboxaldehyde using sodium cyanoborohydride in methanol
followed by deblocking using hydroxylamine hydrochloride in
refluxing ethanol in 63% yield as a hygroscopic solid as the
hydrochloride salt.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 2.72 (m, 2H), 2.83 (m, 2H),
3.61 (s, 4H), 6.46 (d, J=8, 1H), 6.97 (d, J=7, 1H), 7.09 (m, 2H),
7.17 (m, 2H), 7.47 (t, J=8, 1H), 7.54 (m, 2H), 7.74 (m, 2H), 8.41
(m, 4H). .sup.13 C-NMR (CDCl.sub.3, .delta.): 29.7, 53.4, 54.9,
107.7, 110.6, 123.6, 126.9, 129.0, 134.8, 136.6, 139.1, 140.9,
148.3, 149.6, 154.8, 158.0. MS (%): 396 (parent+1, 100). HRMS
Calc'd. for C.sub.25 H.sub.26 N.sub.5 (parent+1): C, 396.2188.
Found: 396.2155.
EXAMPLE 120
6-{4-[2-(Bis-pyridin-4-ylmethyl-amino)-ethyl]-phenyl}-pyridin-2-ylamine
Prepared as in Example 119, using pyridine-4-carboxaldehyde, in 75%
yield, mp 150-163.degree. C. (dec.) as the hydrochloride salt.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 2.70 (m, 2H), 2.81 (m, 2H),
3.60 (s, 4H), 6.42 (d, J=8, 1H), 7.03 (d, J=7, 1H), 7.06 (m, 2H),
7.16 (m, 4H), 7.46 (t, J=8, 1H), 7.81 (m, 2H), 8.46 (m, 4H).
.sup.13 C-NMR (CDCl.sub.3, .delta.): 33.4, 55.4, 57.3, 107.0,
110.6, 123.3, 126.7, 128.9, 137.7, 138.3, 140.3, 148.4, 149.7,
155.7, 158.2. MS (%): 396 (parent+1, 100). HRMS. Calc'd. for
C.sub.25 H.sub.26 N.sub.5 (parent+1): C, 396.2188. Found:
396.2152.
EXAMPLE 121
N-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-N-(1-benzyl-piperidin-4-yl)-a
cetamide
Prepared as in Example 117, using N-benzyl-4-piperidone with sodium
cyanoborohydride in methanol, followed by acetylation with acetyl
chloride and triethylamine in methylene chloride, followed by
deblocking with hydroxylamine hydrochloride in refluxing ethanol in
44% yield, mp 60-70.degree. C. (dec.) as the hydrochloride
salt.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 1.8-1.9 (m, 4H), 2.12 (s, 3H),
2.84 (m, 2H), 2.96 (m, 2H), 3.40 (m, 4H), 3.50 (s, 2H), 4.59 (bs,
2H), 6.42 (t, J=8, 1H), 7.02 (d, J=7, 1H), 7.2-7.4 (m, 7H), 7.45
(dt, J=7,8, 1H), 7.82 (m, 2H). .sup.13 C-NMR (CDCl.sub.3, .delta.):
14.2, 14.7, 22.1, 22.2, 30.0, 30.8, 35.5, 37.6, 43.8, 46.0, 53.0,
53.1, 62.9, 63.0, 107.1, 107.2, 110.8, 126.9, 128.1, 128.2, 128.7,
128.9, 129.2, 129.3, 137.0, 137.7, 137.8, 138.3, 138.4, 138.6,
140.2, 155.7, 156.1, 158.2, 158.3, 170.2, 170.7. FAB MS (%): 429
(parent+1, 44), 91 (100). HRMS Calc'd. for C.sub.27 H.sub.33
N.sub.4 O (parent+1): C, 429.2654. Found: 429.2669.
EXAMPLE 122
6-[4-(4-Methyl-piperazin-1-ylmethyl)-phenyl]-pyridin-2-ylamine
Prepared from (6-(4-formylphenyl)2-(2,5-dimethylpyrrolyl)-pyridine
(Example 112), using N-methylpiperazine with sodium
cyanoborohydride in methanol in 43% yield, followed by deblocking
using hydroxylamine hydrochloride in refluxing ethanol in 78%
yield, mp 240-250.degree. C. (dec.) as the hydrochloride salt.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 2.24 (s, 3H), 2.4-2.5 (m, 8H),
3.49 (s, 2H), 4.66 (bs, 2H), 6.36 (d, J=8, 1H), 7.00 (d, J=7, 1H),
7.34 (m, 2H), 7.41 (t, J=8, 1H), 7.81 (m, 2H). .sup.13 C-NMR
(CDCl.sub.3, .delta.): 46.0, 53.0, 55.1, 62.7, 107.0, 110.7, 126.7,
129.4, 138.3, 138.6, 156.0, 158.4. FAB MS (%): 283 (parent+1, 82),
244 (45), 183 (100). Anal. Calc'd. for C.sub.17 H.sub.22
N.sub.4.3HCl.2H.sub.2 O: C, 47.73, H, 6.83, N, 13.10. Found: C,
47.85, H, 6.78, N, 12.92.
EXAMPLE 123
3-[4-(6-Amino-pyridin-2-yl)-benzyl]-3-aza-bicyclo[3.1.0]hex-6-ylamine
Prepared as in Example 122, using
6-(t-butoxycarbonylamino)-3-aza-bicyclo[3.1.0]hexane in the
reductive amination in 66% yield, and in 75% yield for the
deblocking which included trifluoroacetic acid in methylene
chloride to remove the t-butoxycarbonyl group, mp 189-192.degree.
C. (dec.) as the hydrochloride salt.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 1.28 (bs, 2H), 2.34 (m, 2H),
2.51 (bs, 1H), 2.85 (m, 2H), 3.48 (s, 2H), 3.61 (bs), 6.38 (d, J=8,
1H), 6.90 (d, J=7, 1H), 7.23 (m, 2H), 7.39 (t, J=8, 1H), 7.66 (m,
2H). .sup.13 C-NMR (MeOD.sub.4, .delta.): 25.2, 32.1, 54.4, 58.9,
107.3, 110.9, 126.7, 128.8, 138.4, 138.5, 139.4, 156.0, 158.5. FAB
MS (%): 281 (parent+1, 97), 212 (30), 183 (100). Anal. Calc'd. for
C.sub.17 H.sub.19 N.sub.4.3HCl.1/2H.sub.2 O: C, 70.56, H, 7.31, N,
19.36. Found: C, 70.76, H, 7.15, N, 19.17.
EXAMPLE 124
6-{4-[2-(Bis-cyclohexylmethyl-amino)-ethyl]-phenyl}-pyridin-2-ylamine
Refer to Scheme 2
A. N,N-Dibenzyl(4-bromophenyl)acetamide:
To a 100 mL round-bottomed flask equipped with N.sub.2 inlet were
addied 1.075 g (5 mmol) 4-bromophenylacetic acid, 0.961 mL (5 mmol)
dibenzylamine, 20 mL dry acetonitrile, 10 mg
1-hydroxybenzotriazole, 959 mg (5 mmol) EDAC, and 1.74 mL (12.5
mmol) triethylamine. The reaction was stirred at room temperature
for 36 hr, poured into aqueous sodium bicarbonate solution, and
extracted into ethyl acetate. The organic layer was washed with
water aqueous citrate, water, and brine, dried over sodium sulfate,
and evaporated to give 2.0 g (100%) of an oil which was used
directly.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 3.705 (s, 2H), 4.43 (s, 2H),
4.61 (s, 2H), 7.1-7.4 (m, 14H). .sup.13 C-NMR (CDCl.sub.3,
.delta.): 40.1, 48.5, 50.2, 120.9, 126.3, 127.5, 127.8, 128.3,
128.6, 129.1, 130.7, 130.8, 131.7, 134.0, 136.2, 137.1, 171.1. MS
(%): 393/395 (parent+1, 98/100).
B. N,N-Dibenzyl-2-(4-bromophenyl)ethaneamine:
To a 100 mL round-bottomed flask equipped with condenser and N2
inlet were added the above oil (5 mmol), 25 mL dry tetrahydrofuran,
and 7.5 mL (15 mmol) of a 2.0M solution of borane methyl sulfide in
tetrahydrofuran. The reaction was refluxed 18 hr, cooled, and
evaporated. The residue wais taken up in 25 mL ethanol, and treated
with 1 g sodium carbonate and 1 g cesium fluoride, then refluxed 18
hr. The reaction was cooled, evaporated, and the residue taken up
in water/ethyl acetate. The organic layer was separated, washed
with water and brine, dried over sodium sulfate, and evaporated.
The resulting oil (175 g, 92%) was used directly.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 2.70 (m, 2H), 2.75 (m, 2H),
3.65 (s, 4H), 6.95 (d, J=8, 1H), 7.2-7.4 (m, 13H). .sup.13 C-NMR
(CDCl.sub.3, .delta.): 33.0, 54.8, 58.3, 119.6, 126.9, 128.2,
128.7, 130.7, 131.2, 139.563, 139.635. MS (%): 380/382 (parent+1,
95/100).
C.
2-(2,5-Dimethylpyrrol-1-yl)-6-(4-(2-(N,N-dibenzylamino)ethyl)phenyl)-pyrid
ine:
To a 100 mL three-necked round-bottomed flask equipped with septum
and N2 inlet were added 1.75 g (4.60 mmol) of
N,N-dibenzyl-2-(4-bromophenyl)ethaneamine and 16 mL dry ether. The
solution was cooled to -70.degree. C., and 3.45 mL of a 1.6 M
solution (5.53 mmol) of butyl lithium in hexanes added dropwise
over 5 min. The reaction was stirred 5 min at -70.degree. C., then
warmed to room temperature, and a solution of 0.950 g (5.53 mmol)
2-(2,5-dimethylpyrrol-1-yl)-pyridine in 5 mL dry ether added over 3
min. The reaction turned to dark orange and then dark red as it was
stirred at room temperature for 6 hr, then quenched with aqueous
ammonium chloride. The organic layer was diluted with ethyl acetate
and separated, washed with aqueous ammonium chloride and brine,
dried over sodium sulfate for 14 hr in the air (to permit air
oxidation to the pyridine) and evaporated. The residue was
chromatograplied on silica gel using 10% ethyl acetate in hexane as
eluant to afford the product as an oil, 860 mg (40%).
.sup.1 H-NMR (CDCl.sub.3, .delta.): 2.45 (s, 6H), 2.94 (m, 2H),
3.04 (m, 2H), 3.84 (s, 4H), 6.18 (s, 2H), 7.24 (d, J=8, 1H),
7.3-7.5 (m, 12H), 7.83 (d, J=8, 1H), 7.92 (t, J=8, 1H), 8.17 (m,
2H). .sup.13 C-NMR (CDCl.sub.3, .delta.): 13.8, 33.5, 55.1, 58.5,
107.3, 118.2, 119.7, 127.0, 128.4, 128.8, 128.9, 129.1, 129.5,
138.7, 139.85, 142.4, 151.8, 157.0. MS (%): 472 (parent+1,
100).
D.
2-(2,5-Dimethylpyrrol-1-yl)-6-(4-(2-aminoethyl)phenyl)-pyridine:
To a 100 mL three-necked round-bottomed flask equipped with septum
and N2 inlet were added 860 mg (1.826 inmol)
2-(2,5-dimethylpyrrol-1-yl)-6-(4-(2-(N,N-dibenzylamino)ethyl)phenyl)-pyrid
ine, 576 mg (9.13 mmol, 5 eq.) ammonium formate, 20 mL ethanol, and
100 mg 10% Pd-C. The reaction was refluxed 2 hr, and additional
portion of ammonium formate and palladium added, and refluxing
continued another 1 hr. The icooled reaction was filtered through
Celite using ethanol and methylene chloride, and the filtrate
evaporated. The residue was taken up in aqueous sodium bicarbonate
solution and ethyl acetate, the aqueous layer reextracted with
ethyl acetate, and the organic layer separated and washed with
brine, dried over sodium sulfate, and evaporated. The crude oil,
430 mg (81%) was used directly.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 2.20 (s, 6H), 2.4 (bs, 2H),
2.80 (m, 2H), 2.98 (m, 2H), 5.91 (s, 2H), 7.09 (d, J=8, 1H), 7.26
(m, 2H), 7.69 (d, J=8, 1H), 7.82 (t, J=8, 1H), 7.99 (m, 2H).
.sup.13 C-NMR (CDCl.sub.3, .delta.): 14.2, 39.3, 43.2, 60.4, 106.9,
118.1, 119.7, 127.0, 129.3, 136.5, 138.6, 141.0, 151.6, 156.7. MS
(%): 292 (parent+1, 100).
E.
2-(2,5-Dimethylpyrrol-1-yl)-6-{4-[2-(bis-cyclohexylmethyl-amino)-ethyl]-ph
enyl}-pyridine:
To a 100 mL round-bottomed flask equipped with N.sub.2 inlet were
added 215 mg (0.739 mmol)
2-(2,5-dimethylpyrrol-1-yl)-6-(4-(2-aminoethyl)phenyl)-pyridine,
179 uL (1.48 mmol) cyclohexanecarboxaldehyde, 7 mL methanol, and 93
mg (1.48 mmol) sodium cyanoborohydride. The reaction was stirred at
room temperature for 18 h, poured into dilute aqueous sodium
bicarbonate solution, and extracted into ethyl acetate. The organic
layer was washed with water and brine, dried over sodium sulfate,
and evaporated. The residue was chromatographed on silica gel using
ethyl acetate/hexane as eluant to afford the product, 134 mg
(37.5%) as an oil.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 0.84 (m, 4H), 1.20 (m, 6H),
1.40 (m, 2H), 1.69 (m, 6H), 1.78 (m, 2H), 2.2 (m, 6H), 2.24 (s,
6H), 2.63 (m, 2H), 2.76 (m, 2H), 5.96 (s, 2H), 7.12 (d, J=8, 1H),
7.30 (m, 2H), 7.73 (d, J=8, 1H), 7.85 (t, J=8, 1H), 8.01 (m, 2H).
.sup.13 C-NMR (CDCl.sub.3, .delta.): 13.5, 26.3, 27.0, 31.9, 33.5,
36.4, 57.2, 62.4, 106.9, 118.0, 119.5, 126.8, 128.7, 129.3, 135.9,
138.5, 143.0, 151.6, 157.0. MS (%): 484 (parent+1, 100).
F.
6-{4-[2-(Bis-cyclohexylmethyl-amino)-ethyl]-phenyl}-pyridin-2-ylamine:
To a 100 mL round-bottomed flask equipped with condenser and
N.sub.2 inlet were added 134 mg (0.277 mmol)
2-(2,5-dimethylpyrrol-1-yl)-6-{4-[2-(bis-cyclohexylmethyl-amino)-ethyl]-ph
enyl}-pyridine, 96 mg (1.387 mmol) hydroxylamine hydrochloride, 1
mL water and 5 mL ethanol. The solution was heated at 80.degree. C.
for 35 h, cooled, and poured into dilute aqueous hydrochloric acid.
The aqueous layer washed with ethyl acetate, the pH adjusted to 11
with 1 N sodium hydroxide solution, and extracted with ethyl
acetate. The organic layer was washed with brine, dried over sodium
sulfate, and evaporated. The resulting oil was taken up in ether
and precipitated using 1 N HCl in ether. The product was collected
as a tan solid, mp 75-85.degree. C., 68 mg (51%).
.sup.1 H-NMR (CDCl.sub.3, .delta.): 0.81 (m, 6H), 1.24 (m, 6H),
1.38 (m, 2H), 1.66 (m, 6H), 1.74 (m, 2H), 2.17 (d, J=7, 4H), 2.60
(m, 2H), 2.70 (m, 2H), 4.55 (bs, 2H), 6.40 (d, J=8, 1H), 7.04 (d,
J=7, 1H), 7.23 (m, 2H), 7.45 (t, J=8, 1H), 7.81 (m, 2H). .sup.13
C-NMR (CDCl.sub.3, .delta.): 26.3, 27.0, 31.9, 33.4, 36.4, 57.2,
62.4, 106.8, 110.7, 126.7, 129.0, 137.2, 138.3, 142.0, 156.2,
158.3. MS (%): 406 (parent+1, 100). Anal. Calc'd. for C.sub.27
H.sub.39 N.sub.3.2HCl.2H.sub.2 O: C, 63.02, H, 8.81, N, 8.17.
Found: C, 62.54, H, 8.92, N, 8.56.
EXAMPLE 125
6-{4-[2-(4-Phenyl-butylamino)-ethyl]-phenyl}-pyridin-2-ylamine
A.
N-(2-(2,5-Dimethylpyrrol-1-yl)-6-ethyl]-phenyl}-pyridyl)-(3-phenylbutyrami
de):
To a 100 mL round-bottomed flask equipped with N.sub.2 inlet were
added 200 mg (0.687 mmol)
2-(2,5-dimethylpyrrol-1-yl)-6-(4-(2-aminoethyl)phenyl)-pyridine
(Example 100D), 113 mg (0.687 mmol) 3-phenylbutyric acid, 132 mg
(0.687 mmol) EDAC, 10 mg N-hydroxybenzotriazole, 5 mL dry
acetonitrile, and 211 uL (1.51 mmol) triethylamine. The reaction
was stirred at room temperature for 12 h, poured into dilute
aqueous citrate solution, and extracted into ethyl acetate. The
organic layer was washed with water, aqueous sodium bicarbonate
solution, and brine, dried over sodium sulfate, and evaporated. The
resulting yellow oil, 300 mg (100%) was used directly.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 1.28 (m, 2H), 2.23 (s, 6H),
2.61 (m, 2H), 2.85 (m, 4H), 3.51 (m, 2H), 5.95 (s, 2H), 7.1-7.4 (m,
8H), 7.70 (d, J=8, 1H), 7.85 (t, J=8, 1H), 8.00 (m, 2H). .sup.13
C-NMR (CDCl.sub.3, .delta.): 13.5, 27.1, 35.2, 35.5, 35.8, 40.4,
107.0, 118.2, 119.8, 125.9, 127.2, 128.4, 128.5, 128.6, 129.2,
136.7, 138.0, 140.5, 141.5, 151.7, 156.6, 172.8. MS (%): 438
(parent+1, 100).
B2-(2,5-Dimethylpyrrol-1-yl)-6-{4-[2-(4-phenylbutyl)-ethyl]-phenyl}-pyridin
e:
To a 100 mL round-bottomed flask equipped with condenser and
N.sub.2 inlet were added 300 mg (0.687 mmol)
N-(2-(2,5-dimethylpyrrol-1-yl)-6-ethyl]-phenyl}-pyridyl)-(3-phenylbutyrami
de), 10 mL dry tetrahydrofuran, and 1.0 mL (2.06 mmol) of a 2.0 M
solution of borane methyl sulfide in tetrahydrofuran. The reaction
was refluxed 20 h, cooled, and evaporated. The riesidue was taken
up in 40 mL ethanol, treated with 1 g sodium carbonate and 0.5 g
cesium fluoride, and refluxed 40 h. The reaction was cooled and
evaporate, and the residue taken up in ethyl acetate/water. The
organic layer was separated, washed with water and brine, dried
over sodium sulfate, and evaporated. The residue was
chromatographed on silica gel using methanol/methylene chloride as
eluant to afford the product as a low-melting solid, 13 mg
(4.5%).
.sup.1 H-NMR (CDCl.sub.3, .delta.): 1.67 (m, 2H), 1.97 (m, 2H),
2.18 (s, 6H), 2.58 (m, 2H), 2.93 (m, 2H), 3.14 (m, 2H), 3.25 (m,
2H), 5.91 (s, 2H), 7.1-7.3 (m, 8H), 7.66 (d, J=8, 1H), 7.82 (t,
J=8, 1H), 7.96 (m, 2H). .sup.13 C-NMR (CDCl.sub.3, .delta.): 13.4,
26.1, 28.6, 33.8, 35.3, 47.9, 49.0, 107.0, 118.2, 119.9, 126.0,
127.4, 128.3, 128.4, 129.1, 138.2, 138.6, 141.4, 151.7, 156.4. MS
(%): 424 (parent+1, 100).
C.
6-{4-[2-(4-Phenyl-butylamino)-ethyl]-phenyl}-pyridin-2-ylamine:
To a 100 mL round-bottomed flask equipped with condenser and
N.sub.2 inlet were added 13 mg (0.0307 mmol)
2-(2,5-dimethylpyrrol-1-yl)-6-{4-[2-(4-phenylbutyl)-ethyl]-phenyl}-pyridin
e, 21 mg (0.307 mmol) hydroxylamine hydrochloride, 4 mL ethanol,
and 1 mL water. The reaction was refluxed 40 h, cooled, and poured
into water and extracted into ethyl acetate. The organic layer was
separated, washed with water and brine, dried over sodium sulfate,
and evaporated. The residue was taken up in ether and precipitated
with 1 N HCl in ether to afford a hygroscopic solid, 3 mg
(23%).
.sup.1 H-NMR (CDCl.sub.3, .delta.): 1.49 (m, 2H), 1.59 (m, 2H),
2.59 (m, 4H), 2.84 (m, 4H), 4.54 (bs, 2H), 6.42 (d, J=8, 1H), 7.03
(d, J=7.5, 1H), 7.14 (m, 2H), 7.24 (m, 5H), 7.46 (t, J=8, 1H), 7.82
(m, 2H). .sup.13 C-NMR (CDCl.sub.3, .delta.): 29.1, 29.6, 35.8,
35.9, 49.6, 50.9, 106.9, 110.8, 125.6, 126.9, 127.1, 128.2, 128.4,
128.9, 138.3, 140.5, 142.4, 156.1, 158.2. MS (%): 346 (parent+1,
100).
EXAMPLE 126
6-{4-[2-(5-Phenyl-pentylamino)-ethyl]-phenyl}-pyridin-2-ylamine
Prepared as in Example 100A, using 4-phenyl pentanoic acid, with a
45% yield in the final step, as a solid, mp 60-70.degree. C.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 1.31 (m, 2H), 1.50 (m, 2H),
1.60 (m, 2H), 2.58 (m, 4H), 2.87 (m, 4H), 4.49 (bs, 2H), 6.42 (d,
J=8, 1H), 7.04 (d, J=7, 1H), 7.14 (m, 2H), 7.24 (m, 5H), 7.47 (t,
J=8, 1H), 7.83 (m, 2H). .sup.13 C-NMR (CDCl.sub.3, .delta.): 26.9,
29.6, 31.3, 35.8, 49.6, 50.9, 106.9, 110.7, 125.6, 126.9, 128.2,
128.4, 128.9, 137.8, 138.3, 142.6, 158.2. MS (%): 360 (parent+1,
100).
EXAMPLE 127
6-{4-[3-(1,2,3,4-Tetrahydro-naphthalen-2-ylamino)-propyl]-phenyl}-pyridin-2
-ylamine
Prepared using
2-(2,5-dimethylpyrrol-1-yl)-6-(4-(3-aminopropyl)phenyl)-pyridine,
which was prepared as in Example 100, starting from
3-(4-bromophenyl)-propionic acid, which was prepared as follows: To
a 500 mL round-bottomed flask equipped with addition funnel ancl
N.sub.2 inlet were added 45 mL formic acid, which was cooled to
0.degree. C., followed by dropwise addition of 67 mL triethylamine.
The resulting solution was warmed to room temperature, followed by
addition of 9.25 g (50 mmol) of 4-bromobenzaldehyde and 7.21 g (50
mmol) of Meldrum's acid. The reaction was heated to 95.degree. C.
over 1 h, then heated at 95-100.degree. C. for 2 h. The reaction
was cooled, poured into ice/water, arid the pH adjusted to 1 with 6
N hydrochloric acid. The mixture was let stand at 0.degree. C. for
14 h, and the precipitate collected, washed with water, and taken
up in ethyl acetate and extracted with aqueous sodium bicarbonate
solution. The aqueous layer was washed with ethyl acetate, then the
pH adjusted to 1 with 6 N hydrochloric acid followed by extraction
with ethyl acetate. The organic layer was washed with brine, dried
over sodium sulfate, and evaporated to a solid, 4.56 g (40%).
.sup.1 H-NMR (CDCl.sub.3, .delta.): 2.66 (t, J=7, 2H), 2.92 (t,
J=7, 2H), 7.1 (m, 2H), 7.45 (m, 2H). .sup.13 C-NMR (CDCl.sub.3,
.delta.): 29.9, 35.3, 120.2, 130.0, 131.6, 139.0, 178.8.
The remaining steps were carried out following Example 124 to make
2-(2,5-dimethylpyrrol-1-yl)-6-(4-(3-amincpropyl)phenyl)-pyridine,
which was then converted as follows: To a 100 mL round-bottomed
flask equipped with N.sub.2 inlet were added 300 mg (0.984 mmol)
2-(2,5 dimethylpyrrol-1-yl)-6-(4-(3-aminopropyl)phenyl)-pyridine,
156 uL (1.18 mmol) 1,2,3,4-tetrahydronapthalen-2-one, 7 mL
methanol, and 74 mg (1.18 mmol) sodium cyanoborohydride, followed
by 3 mL of 1 N HCl in methanol. The reaction was stirred at room
temperature for 6 h, poured into aqueous sodium bicarbonate
solution, and extracted into ethyl acetate. The organic layer was
washed with water and brine, dried over sodium sulfate, and
evaporated. The residue was chromatographed on silica gel using
methanol/methylene chloride as eluant to afford
2-(2,5-dimethylpyrrolyl)-6-{4-[3-(1,2,3,4-tetrahydro-naphthalen-2-ylamino)
-propyl]-phenyl}-pyridine as an oil, 120 mg (28%).
.sup.1 H-NMR (CDCl.sub.3, .delta.): 1.70 (m, 1H), 1.99 (m, 2H),
2.11 (m, 1H), 2.205 (s, 6H), 2.7-2.9 (m, 6H), 3.04 (m, 3H), 3.6
(bs, 1H), 5.92 (s, 2H), 7.0-7.2 (m, 5H), 7.27 (m, 2H), 7.69 (d,
J=8, 1H), 7.84 (t, J=8, 1H), 7.96 (m, 2H). .sup.13 C-NMR
(CDCl.sub.3, .delta.): 13.5, 27.9, 28.4, 30.5, 33.2, 45.9, 54.0,
106.9, 118.1, 119.6, 125.8, 126.0, 127.0, 128.6, 128.8, 129.3,
134.2, 138.6, 142.9, 151.6, 156.8. MS (%): 436 (parent+1, 100).
The oil was taken up 5 mL ethanol and 1 mL water and treated with
96 mg (1.38 mmol, 5 eq.) hydroxylamine hydrochloride at 80.degree.
C. for 36 h. The reaction was cooled, poured into dilute aqueous
hydrochloric acid, and washed with ethyl acetate. The pH of the
aqueous layer was adjusted to 10 with 1 N sodium hydroxide solution
followed by extraction with ethyl acetate. The organic layer was
washed with brine, dried over sodium sulfate, and evaporated to
afford an oil, 65 mg (66%), which was converted to the
hydrochloride sailt using HCl in ether, mp 120-130.degree. C.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 1.57 (m, 2H), 1.87 (m, 2H),
2.6-3.0 (m, 9H), 4.58 (bs, 2H), 6.40 (d, J=8, 1H), 7.0-7.1 (m, 5H),
7.25 (m, 2H), 7.46 9t, J=8, 1H), 7.83 (m, 2H). .sup.13 C-NMR
(CDCl.sub.3, .delta.): 28.1, 29.6, 31.9, 33.5, 36.8, 46.6, 53.6,
106.9, 110.7, 125.7, 125.8, 126.8, 128.6, 128.7, 129.4, 135.3,
136.3, 137.4, 138.4, 142.6, 156.1, 158.3. MS (%): 358 (parent+1,
100). Anal. Calc'd. for C.sub.24 H.sub.27 N.sub.3.2HCl.2/3H.sub.2
O: C, 65.15, H, 6.91, N, 9.50. Found: C, 65.01, H, 7.10, N,
9.22.
EXAMPLE 128
6-{4-[2-(4-Phenethyl-piperazin-1-yl)-ethyl]-phenyl}-4-methyl-pyridin-2-ylam
ine Refer to Scheme 3
A. ((4-Iodophenyl)acetyl)-phenethylgiperazine:
To a 100 mL round-bottomed flask equipped with N.sub.2 inlet were
added 1.0 g (3.816 mmol) 4-iodophenylacetic acid, 725 mg (3.816
mmol) phenethylpiperazine, 10 mL dry acetonitrile, 10 mg
1-hydroxybenzotriazole, 732 mg (3.816 mmol) EDAC, and 1.17 mL
(8.395 mmol) triethylamine. The reaction was sitirred at room
temperature for 16 hr, evaporated, and chromatographed on silica
gel using methanol/methylene chloride as eluant to afford 1.74 g
(100%) of a low-melting solid.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 2.34 (m, 2H), 2.45 (m, 2H),
2.58 (m, 2H), 2.75 (m, 2H), 3.43 (m, 2H), 3.63 (s, 2H), 3.65 (m,
2H), 6.97 (m, 2H), 7.17 (m, 3H), 7.25 (m, 2H), 7.62 (m, 2H).
.sup.13 C-NMR (CDCl.sub.3, .delta.): 33.5, 40.2, 41.8, 46.0, 52.7,
53.2, 60.1, 92.2, 126.1, 128.4, 128.5, 128.7, 130.8, 134.8, 137.7,
139.95, 168.7. MS (%): 435 (parent+1, 100).
B. ((4-Iodophenyl)ethyl)-phenethylpiperazine:
To a 100 mL round-bottomed flask equipped with condenser and N2
inlet were added 1.66 g (3.8 mmol)
((4-iodophenyl)acetyl)-phenethylpiperazine, 15 mL dry
tetrahydrofuran, and 5.73 mL (11.46 mmol) of a 2.0 M solution of
borane methyl sulfide in tetrahydrofuran. The reaction was refluxed
18 hr, cooled, and evaporated. The residue was taken up in 25 mL
ethanol, and treated with 1 g sodium carbonate and 1 g cesium
fluoride, then refluxed 18 hr. The reaction was cooled, evaporated,
and the residue taken up in water/ethyl acetate. The organic layer
was separated, washed with water and brine, dried over sodium
sulfate, and evaporated. The resulting solid, mp 91-93.degree. C.
(0.74 g, 46%) was used directly.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 2.5-2.7 (m, 12H), 2.71 (m, 2H),
2.77 (m, 2H), 6.94 (m, 2H), 7.19 (m, 3H), 7.26 (m, 2H), 7.58 (m,
2H). .sup.13 C-NMR (CDCl.sub.3, .delta.): 33.1, 33.6, 53.2, 60.2,
60.6, 91.1, 126.0, 128.4, 128.7, 130.8, 137.4, 140.0, 140.3. MS
(%): 420 (parent+1, 100).
C. 2-(2,5-Dimethylpyrrolyl)-4-methylpyridine:
To a 250 mL round-bottomed flask equipped with condenser were added
10.8 g (100 mmol) 2-aminopyridine, 11.7 mL (100 mmol)
hexane-2,5-dione, and 0.5 mL concentrated hydrochloric acid. The
reaction was heated slowly to 150.degree. C. over 2 hr, then at
165-170.degree. C. for 2 hr, and cooled. The residue was poured
into aqueous sodium bicarbonate solution, extracted into ethyl
acetate, and the organic layer washed with water and brine, dried
over sodium sulfate, and evaporated. The residue was
chromatographed on silica gel using ethyl acetate in hexane as
elijant to afford a low-melting solid, 15.36 g (83%).
.sup.1 H-NMR (CDCl.sub.3, .delta.): 2.11 (s, 6H), 2.41 (s, 3H),
5.87 (s, 2H), 7.02 (bs, 1H), 7.10 (m, 1H), 8.44 (d, J=5, 1H).
.sup.13 C-NMR (CDCl.sub.3, .delta.): 13.1, 21.0, 106.7, 122.75,
123.4, 128.5, 149.0, 149.4, 152.2. MS (%): 187 (parent+1, 100).
D.
2-(2,5-Dimethylpyrrol-1-yl)-4-methyl-6-(4-(2-(phenethylpiperazin-4-yl)ethy
l)phenyl)-pyridine:
To a 100 mL three-necked round-bottomed flask equipped with septum
and N.sub.2 inlet were added 440 mg (1.05 mmol) of
((4-iodophenyl)ethyl)-phenethylpiperazine and 5 mL dry ether. The
solution was cooled to -70.degree. C., and 0.625 mL of a 1.6 M
solution (1.0 mmol) of butyl lithium in hexanes added dropwise over
5 min. The reaction was stirred 5 min at -70.degree. C., then
warmed to room temperature, and a solution of 186 mg (1.0 mmol)
2-(2,5-dimethylpyrrol-1-yl)-4-methyl-pyridine in 5 mL dry ether
added over 3 min. The reaction turned to dark orange and then dark
red as it was stirred at room temperature for 5 hr, then quenched
with aqueous ammonium chloride. The organic layer was diluted with
ethyl acetate and separated, washed with aqueous ammonium chloride
and brine, dried over sodium sulfate for 14 hr in the air (to
permit air oxidation to the pyridine) and evaporated. The residue
was chromatographed on silica gel using aqueous acetonitrile as
eluant to afford the product as an oil, 165 mg (34.5%).
.sup.1 H-NMR (CDCl.sub.3, .delta.): 2.19 (s, 6H), 2.45 (s, 3H),
2.6-2.9 (m, 16H), 5.90 (s, 2H), 6.93 (m, 2H), 7.20 (m, 3H), 7.27
(m, 3H), 7.57 (m, 2H), 7.96 (d, J=8, 1H). .sup.13 C-NMR
(CDCl.sub.3, .delta.): 13.5, 21.3, 33.0, 33.5, 53.0, 60.0, 60.4,
106.7, 119.2, 120.5, 126.1, 127.0, 128.4, 128.6, 128.7, 129.1,
130.8, 137.4, 139.8, 140.1, 151.8, 156.5. MS (%): 479 (parent+1,
100).
E.
6-(4-(2-(Phenethypiperazin-4-yl)ethyl)phenyl)-4-methyl-pyridinyl-2-amine:
To a 100 mL three-necked round-bottomed flask equipped with septum
and N.sub.2 inlet were added 165 mg (0.345 mmol)
2-(2,5-dimethylpyrrol-1-yl)-4-methyl-6-(4-(2-(phenethylpiperazin-4-yl)ethy
l)phenyl)-pyridine, 120 mg (1.726 mmol) hydroxylamine
hydrochloride, 1 mL water, and 5 mL ethanol. The reaction was
refluxed 14 hr, cooled, evaporated, and taken up in ethyl acetate.
The organic layer was washed with water and brine, dried over
sodium sulfate, and evaporated. The residue was chromatographed on
silica gel usirg methanol/methylene chloride as eluant to afford an
oil, which was converted to thie hydrochloride salt using 1 N HCl
in ether to give 18 mg (10%), mp 242-250.degree. C.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 2.22 (s, 3H), 2.63 (m, 4H),
2.79 (m, 12H), 6.24 (s, 1H), 6.80 (s, 1H), 7.1-7.3 (m, 7H), 7.71
(m, 2H). .sup.13 C-NMR (CDCl.sub.3, .delta.): 21.1, 32.8, 33.0,
52.6, 59.9, 60.1, 107.7, 112.6, 126.2, 127.0, 128.4, 128.6, 128.8,
139.5, 140.2, 149.8, 158.4. MS (%): 401 (parent+1, 100).
EXAMPLE 129
6-{4-[3-(4-Phenethyl-piperazin-1-yl)-propyl]-phenyl}-pyridin-2-ylamine
Prepared as in Example 128, starting from
3-(4-bromophenyl)-propionic acid, prepared in Example 125,
concluding with deblocking with hydroxylamine hydrochloride,
affording a residue which was purified by column chromatography
using methanol/methylene chloride to give a 46% yield of an oil,
which was converted to the hydrochloride salit using 1 N HCl in
ether to give mp 125-140.degree. C.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 1.87 (m, 2H), 2.40 (m, 4H),
2.5-2.7 (m, 10H), 2.81 (m, 2H), 4.73 (bs, 2H), 6.38 (d, J=8, 1H),
7.01 (d, J=7.5, 1H), 7.1-7.3 (m, 7H), 7.44 (t, J=8, 1H), 7.80 (m,
2H). .sup.13 C-NMR (CDCl.sub.3, .delta.): 28.3, 32.7, 33.5, 53.0,
57.95, 60.5, 107.0, 110.7, 126.0, 126.9, 128.4, 128.6, 137.3,
138.0, 138.4, 140.3, 142.6, 156.2, 158.4. MS (%): 401 (parent+1,
100). Anal. Calc'd. for C.sub.26 H.sub.32 N.sub.4.3HCl.H.sub.2 O:
C, 59.15, H, 7.06, N, 10.61. Found: C, 58.67, H, 7.02, N,
11.23.
EXAMPLE 130
6-{3-[2-(4-Phenethyl-piperazin-1-yl)-ethyl]-phenyl}-pyridin-2-ylamine
Prepared using the procedures in Example 1, with 3-aminophenethyl
alcohol as starting material, with the final condensation step
proceeding in 25% yield after chromatography on silica gel using
methanol/methylene chloride as eluant. The product was precipitated
from ether as the hydrochloride salt using 1 N HCl in ether, mp
120.degree. C. (dec.).
.sup.1 H-NMR (.delta., CDCl.sub.3): 2.5-2.7 (m, 12H), 2.80 (m, 2H),
2.87 (m, 2H), 4.54 (bs, 2H), 6.41 (d, J=8, 1H), 7.05 (d, J=7, 1H),
7.20 (m, 4H), 7.25 (m, 2H), 7.33 (t, J=8, 1H), 7.46 (t, J=8, 1H),
7.73 (m, 1H), 7.78 (s, 1H). .sup.13 C-NMR (.delta., CDCl.sub.3):
33.6, 33.7, 53.2, 60.5, 60.6, 107.1, 111.0, 124.6, 126.0, 127.2,
128.4, 128.6, 128.7, 129.0, 138.3, 139.8, 140.3, 140.6, 156.2,
158.3. MS (%): 387 (parent+1, 100). Anal. Calc'd. for C.sub.25
H.sub.30 N.sub.4.2HCl.1/2CH.sub.2 Cl.sub.2.H.sub.2 O: C, 58.91, H,
6.19, N, 10.78. Found: C, 59.22, H, 6.64, N, 10.38.
EXAMPLE 131
6-{4-[2-(4-Amino-2,6-dimethyl-piperidin-1-yl)-ethyl]-phenyl}-pyridin-2-ylam
ine (cis diastereomer)
Prepared as in Example 108, using the trans isomer of
N-benzyl-2,6-dimethylpiperidin-4-one from Example 108A, with the
final step in 92% yield, as the hydrochloride salt.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 1.05 (m, 6H), 1.47 (m, 2H),
1.71 (m, 2H), 2.54 (m, 2H), 2.71 (m, 2H), 2.83 (m, 2H), 3.34 (m,
1H), 4.49 (bs, 2H), 6.41 (d, J=8, 1H), 7.05 (d, J=8, 1H), 7.25 (m,
2H), 7.46 (t, J=8, 1H), 7.82 (m, 2H). .sup.13 C-NMR (CDCl.sub.3,
.delta.): 11.3, 21.4, 35.6, 41.4, 44.1, 45.5, 48.8, 51.1, 51.2,
106.8, 110.7, 126.7, 128.9, 137.5, 138.3, 141.5, 156.1, 158.2. FAB
MS (%): 325 (parent+1, 4), 279 (20), 167 (45), 149 (100), 113 (36).
HRMS Calc'd. for C.sub.20 H.sub.29 N.sub.4 (parent+1): 325.2392.
Found: 325.2369.
EXAMPLE 132
6-{4-[2-(4-Amino-2,6-diisopropyl-piperidin-1-yl)-ethyl]-phenyl}-pyridin-2-y
lamine (cis diastereomer)
Prepared as in Example 108 using isopropanal, to afford the product
as an oil in 90% yield in the final step, which was converted to
the hydrochloride salt-as an amorphous solid.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 0.8-1.0 (m, 12H), 1.60 (m, 4H),
1.84 (m, 2H), 2.13 (m, 1H), 2.37 (m, 1H), 2.51 (m, 1H), 2.65 (m,
2H), 2.76 (m, 2H), 4.54 (bs, 2H), 6.39 (d, J=8, 1H), 7.03 (d, J=8,
1H), 7.21 (m, 2H), 7.44 (t, J=8, 1H), 7.81 (m, 2H). .sup.13 C-NMR
(CDCl.sub.3, .delta.): 20.6, 20.8, 21.1, 27.1, 29.6, 29.9, 33.9,
36.6, 46.2, 47.8, 60.4, 63.0, 106.7, 110.6, 126.6, 128.9, 137.2,
138.2, 141.5, 156.0, 158.2. APCI MS (%): 381 (parent+1, 100).
EXAMPLE 133
6-{4-[2-(4-Isobutyl-piperazin-1-yl)-1-methyl-ethyl]-phenyl}-pyridin-2-ylami
ne
A.
2-(2,5-Dimethylpyrrolyl)-6-((4-(1-cyanoethyl)phenyl))-pyridine:
To a 100 mL round-bottomed flask equipped with septum and N.sub.2
inlet were added 500 mg (1.74 mmol)
2-(2,5-dimethylpyrrolyl)-6-(4-(cyanomethyl)phenyl))-pyridine
(Example 112) and 17 mL dry tetrahydrofuran. The solution was
cooled to -78.degree. C., and 1.92 mL (1.92 mmol) of a 1.0 M
solution of lithium bistrimethylsilylamide was added dropwise over
3 minutes. After stirring for 15 minutes, 0.23 mL (3.66 mmol)
methyl iodide was added, and stirring continued at -78.degree. C.
for another 15 minutes. The reaction was then poured into aqueous
ammonium chloride and extracted into ethyl acetate. The organic
layer was washed with brine, dried over sodium sulfate, and
evaporated. The residue was chromatographed on silica gel with
hexane/ethyl acetate as eluant to afford 404 mg (77%) of an
oil.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 1.67 (d, J=7, 3H), 2.22 (s,
6H), 3.96 (q, J=7, 1H), 5.95 (s, 2H), 7.17 (d, J=8, 1H), 7.45 (m,
2H), 7.75 (d, J=8, 1H), 7.89 (t, J=8, 1H), 8.10 (m, 2H). .sup.13
C-NMR (CDCl.sub.3, .delta.): 13.5, 21.4, 31.1, 107.1, 118.3, 120.2,
121.4, 127.2, 127.7, 128.7, 138.2, 138.3, 138.8, 141.8, 156.0. IR
(neat, KBr): 2240 (CN). FAB MS (%): 302 (parent+1, 4), 279 (20),
167 (45), 149 (100), 113 (36).
B.
2-(2,5-Dimethylpyrrolyl)-6-((4-(1-carboxyethyl)phenyl))-pyridine:
To a 100 mL round-bottomed flask equipped with condenser and
N.sub.2 inlet were added 400 mg (1.33 mmol)
2-(2,5-dimethylpyrrolyl)-6-((4-(1-cyanoethyl)phenyl))-pyridine and
20 mL ethanol. After heating to reflux, 30 mL of a 10% aqueous
solution of sodium hydroxide was added dropwise slowly, and
refluxing was continued overnight. The reaction was cooled and the
pH adjusted to 1 with 6 N hydrochloric acid, then extracted into
ethyl acetate. The organic layer was washed with brine, dried over
sodium sulfate, and evaporated to a brown solid, mp 149-155.degree.
C., 384 mg (90.5%).
.sup.1 H-NMR (CDCl.sub.3, .delta.): 1.55 (d, J=7, 3H), 2.22 (s,
6H), 3.80 (q, J=7, 1H), 5.95 (s, 2H), 7.14 (d, J=8, 1H), 7.43 (m,
2H), 7.73 (d, J=8, 1H), 7.87 (t, J=8, 1H), 8.05 (m, 2H). .sup.13
C-NMR (CDCl.sub.3, .delta.): 13.5, 18.1, 45.2, 107.0, 118.3, 119.9,
127.3, 128.1, 128.7, 137.5, 138.65, 141.1, 151.7, 156.5, 180.4. FAB
MS (%): 321 (parent+1, 4), 279 (20), 167 (45), 149 (100), 113 (36).
Anal. Calc'd. for C.sub.20 H.sub.20 N.sub.2 O.sub.2.1/4H.sub.2 O:
C, 73.94, H, 6.36, N, 8.62. Found: C, 73.95, H, 6.18, N, 8.41.
C.
2-(2,5-Dimethylpyrrolyl)-6-((4-(1-(4-isobutylpiperazin-1-ylamido)ethyl)phe
nyl))-pyridine:
To a 100 mL round-bottomed flask equipped with condenser and
N.sub.2 inlet were added 187 mg (0.584 mmol)
2-(2,5-dimethylpyrrolyl)-6-((4-(1-carboxyethyl)phenyl))-pyridine,
124 mg (0.584 mmol) N-isobutylpiperazine hydrochloride, 112 mg
(0.584 mmol) N-ethyl-N-3-dimethylaminopropyl-carbodiimide, 79 mg
(0.584 mmol) 1-hydroxybenztriazole, 0.2 mL (1.461 mmol)
triethylamine, and 6 mL acetonitrile. The reaction was stirred at
room temperature for 24 h, poured into aqueous sodium bicarbonate
solution and ethyl acetate. The organic layer was washed with
brine, dried over sodium sulfate, and evaporated. The residue was
chromatographed on silica gel using methanol/methylene chloride as
eluant to afford 218 mg (84%) of an oil.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 0.82 (d, J=7, 6H), 1.45 (d,
J=7, 3H), 1.68 (m, 1H), 1.88 (m, 1H), 1.96 (m, 2H), 2.20 (s, 6H),
2.2 (m, 2H), 2.37 (m, 1H), 3.33 (m, 1H), 3.42 (m, 1H), 3.54 (m,
1H), 3.74 (m, 1H), 3.93 (q, J=7, 1H), 5.92 (s, 2H), 7.12 (d, J=8,
1H), 7.24 (m, 2H), 7.72 (d, J=8, 1H), 7.85 (t, J=8, 1H), 8.01 (m,
2H). .sup.13 C-NMR (CDCl.sub.3, .delta.): 13.5, 20.6, 20.7, 25.3,
42.0, 43.0, 45.5, 53.1, 53.3, 66.5, 107.0, 118.2, 119.8, 127.5,
127.7, 128.6, 136.9, 138.6, 143.5, 151.7, 156.5, 171.7. APCI MS
(%): 445 (parent+1, 100).
D2-(2,5-Dimethylpyrrolyl)-6-{4-[2-(4-isobutyl-piperazin-1-yl)-1-methyl-ethy
l]-phenyl}-pyridine:
To a 100 mL round-bottomed flask equipped with condenser and
N.sub.2 inlet were added 218 mg (0.491 mmol)
2-(2,5-dimethylpyrrolyl)-6-((4-(1-(4-isobutylpiperazin-1-ylamido)ethyl)phe
nyl))-pyridine, 20 mL dry tetrahydrofuran, and 10 mL (20 mmol) of a
2.0 M solution of borane methyl sulfide in tetrahydrofuran. The
solution was refluxed 24 hr, cooled, and the tetrahydrofuran
evaporated. The residue was treated with 25 mL ethanol, 1 g sodium
carbonate, and 300 mg cesium fluoride, and refluxed 24 hr. The
reaction was cooled, poured into 1 N hydrochloric acid, and washed
with ethyl acetate. The aqueous layer was adjusted to pH, 10 with 6
N sodium hydroxide solution and extracted into ethyl acetate. The
organic layer was washed with brine, dried over sodium sulfate, and
evaporated. Both organic layers were collected, and the first one
used subsequently.
APCI MS (%): 431 (parent+1, 100).
E.
6-{4-[2-(4-Isobutyl-piperazin-1-yl)-1-methyl-ethyl]-phenyl}-pyridin-2-ylam
ine:
Prepared using hydroxylamine hydrochloride as in Example 124F.
Purification was effected by making the N-trityl derivative using
triphenylmethyl chloride and triethylamine in methylene chloride at
room temperature overnight, followed by chromatography on silica
gel using methanol/methylene chloride as eluant, and then removal
of the trityl group using 50% aqueous formic acid at 55.degree. C.
for 1 h, followed by filtration, adjustment of the filtrate to pH,
10 with 6 N sodium hydroxide solution, and extraction into ethyl
acetate. The resulting material was converted to the hydrochloride
salt using HCl in ethyl ether to give a white solid, mp
250-260.degree. C., in 17% yield.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 0.86 (d, J=7, 6H), 1.26 (d,
J=6, 3H), 1.74 (m, J=7, 1H), 2.04 (d, J=7, 2H), 2.37 (m, 6H), 2.47
(d, J=7, 2H), 2.97 (m, 1H), 4.48 (bs, 2H), 6.40 (d, J=8, 1H), 7.03
(d, J=7.5, 1H), 7.25 (m, 2H), 7.46 (t, J=8, 1H), 7.82 (m, 2H).
.sup.13 C-NMR (CDCl.sub.3, .delta.): 20.1, 20.9, 25.3, 37.2, 53.5,
66.0, 66.9, 106.7, 110.7, 126.7, 127.3, 127.8, 137.5, 138.2, 146.9,
156.1, 158.1. APCI MS (%): 353 (parent+1, 100). Anal. Calc'd. for
C.sub.22 H.sub.32 N.sub.4.3HCl.3/2H.sub.2 O.1/2(C.sub.4 H.sub.10
O): C, 55.12, H, 7.71, N, 10.71. Found: C, 55.47, H, 8.10, N,
10.52.
EXAMPLE 134
6-{4-[1-Benzyl-2-(4-isobutyl-piperazin-1-yl)-ethyl]-phenyl}-pyridin-2-ylami
ne
Prepared as in Example 133 using benzyl bromide in the alkylation
analogous to Example 133A in 13% yield for the final deblocking
step, converted to the hydrochloride salt in ether.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 0.86 (d, J=6, 6H), 1.73 (m,
J=6, 1H), 2.03 (d, J=7, 2H), 2.37 (m, 6H), 2.53 (m, 3H), 2.69 (m,
1H), 2.83 (m, 1H), 3.14 (m, 2H), 4.465 (bs, 2H), 6.40 (d, J=8, 1H),
6.97 (m, 2H), 7.03 (d, J=7.5, 1H), 7.13 (m, 5H), 7.45 (t, J=8, 1H),
7.78 (m, 2H). .sup.13 C-NMR (CDCl.sub.3, .delta.): 20.9, 25.3,
40.6, 45.1, 53.4, 53.5, 63.7, 66.8, 106.7, 110.7, 125.6, 126.5,
127.9, 128.1, 129.1, 137.4, 138.2, 140.4, 144.5, 156.0, 158.1. APCI
MS (%): 429 (parent+1, 100). Anal. Calc'd. for C.sub.28 H.sub.36
N.sub.4.3HCl.H.sub.2 O.1/2(C.sub.4 H.sub.10 O): C, 60.76, H, 7.82,
N, 9.45, Found: C, 61.14, H, 7.93, N, 9.17.
EXAMPLE 135
6-[4-(Phenethylamino-methyl)-phenyl]-pyridin-2-ylamine
A. 2-(2,5-Dimethylpyrrolyl)-6-(4-carboxyphenyl)-pyridine:
Prepared as in Example 112A, using 4-carboxyphenyl boronic acid, in
22% yield, as a low-melting solid.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 2.22 (s, 6H), 5.94 (s, 2H),
7.21 (d, J=8, 1H), 7.81 (d, J=8, 1H), 7.92 (t, J=8, 1H), 8.18 (m,
4H). APCI MS (%): 293 (parent+1, 100).
B.
2-(2,5-Dimethylpyrrolyl)-6-(4-(N-phenethylcarboxamido)phenyl)-pyridine:
Prepared as in Example 108F, using the above and phenethylamine, in
70% yield, as a low-melting yellow solid.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 2.20 (s, 6H), 2.95 (t, J=7,
2H), 3.73 (dt, J=5,7, 2H), 5.925 (s, 2H), 6.17 (broad triplet, J=5,
1H), 7.17 (d, J=8, 1H), 7.24 (m, 3H), 7.31 (m, 2H), 7.78 (m, 3H),
7.89 (t, J=8, 1H), 8.10 (m, 2H). APCI MS (%): 396 (parent+1,
100).
C. 6-(4-(N-phenethylcarboxamido)phenyl)-pyridin-2-ylamine:
Prepared as in Example 1F, in 36% yield, as a low-melting tan
solid.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 2.94 (t, J=7, 2H), 3.72 (dt,
J=5,7, 2H), 4.93 (bs, 2H), 6.175 (m, 1H), 6.52 (d, J=8, 1H), 7.09
(d, J=7, 1H), 7.24 (m, 3H), 7.31 (m, 2H), 7.54 (t, J=8, 1H), 7.75
(m, 2H), 7.97 (m, 2H). APCI MS (%): 318 (parent+1, 100).
D. 6-[4-(Phenethylamino-methyl)-phenyl]-pyridin-2-ylamine:
Prepared as in Example 133D in 61% yield, mp 236-238.degree. C., as
the hydrochloride salt.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 2.81-2.85 (m, 2H), 2.88-2.92
(m, 2H), 3.84 (s, 2H), 4.47 (bs, 2H), 6.43 (d, J=8, 1H), 7.05 (d,
J=8, 1H), 7.18-7.29 (m, 3H), 7.24-7.27 (m, 2H), 7.29-7.34 (m, 2H),
7.47 (t, J=8, 1H), 7.86 (d, J=8, 1H). .sup.13 C-NMR (CD.sub.3 OD,
.delta.) 33.3, 49.4, 50.0, 51.7, 112.3, 113.4, 128.3, 129.1, 129.8,
130.0, 132.3, 136.1, 137.8, 145.8, 147.2, 157.4. MS (%): 304
(parent+1, 100).
EXAMPLE 136
6-{4-[(Cyclohexyl-methyl-amino)-methyl]-phenyl}-pyridin-2-ylamine
Prepared as in Example 135 in 43% yield, mp>250.degree. C., as
the hydrochloride salt.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 1.10-1.30 (m, 5H), 1.60-1.63
(m, 1H), 1.63-1.87 (m, 4H), 2.20 (s, 3H), 2.41-2.46 (m, 1H), 3.60
(bs, 2H), 4.48 (bs, 2H), 6.44 (d, J=8, 1H), 7.06 (d, J=8, 1H),
7.41-7.50 (m, 3H), 7.83-7.87 (m, 2H). MS(%): 296 (parent+1,
100).
EXAMPLE 137
6-[4-(4-Amino-piperidin-1-ylmethyl)-phenyl}-pyridin-2-ylamine
Prepared as in Example 135 as an amorphous solid in 25% yield.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 1.30-1.34 (m, 2H), 1.71-1.74
(m, 2H), 1.97-2.00 (m, 2H), 2.57-2.60 (m, 1H), 2.77-2.80 (m, 2H),
3.46 (s, 2H), 6.39 (d, J=8, 1H), 6.94 (d, J=8, 1H), 7.27-7.29 (m,
2H), 7.42 (t, J=8, 1H), 7.70-7.73 (m, 2H). MS (%): 283 (parent+1,
100).
EXAMPLE 138
6-(4-Piperidin-1-ylmethyl-phenyl)-pyridin-2-ylamine
Prepared as in Example 135 in 53% yield, mp>250.degree. C., as
the hydrochloride salt.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 1.40-1.42 (m, 2H), 1.54-1.59
(m, 4H), 2.39 (bs, 4H), 3.51 (s, 2H), 4.50 (bs, 2H), 6.42 (d, J=8,
1H), 7.05 (d, J=8, 1H), 7.36 (d, J=8, 2H), 7.47 (t, J=8, 1H), 7.84
(d, J=8, 2H). .sup.13 C-NMR (CDCl.sub.3, .delta.): 24.2, 25.7,
54.3, 63.4, 106.9, 110.8, 126.5, 129.5, 138.3, 156.0. MS (%): 268
(parent+1, 100).
EXAMPLE 139
6-[4-(Indan-2-ylaminomethyl)-phenyl]-pyridin-2-ylamine
Prepared as in Example 135 in 35% yield, mp 185-187.degree. C., as
the hydrochloride salt.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 2.81 (dd, J.sub.1 =9, J.sub.2
=6, 2H), 3.16 (dd, J.sub.1 =9, J.sub.2 =6, 2H), 3.66-3.69 (m, 1H),
3.89 (s, 2H), 4.48 (bs, 2H), 6.42 (d, J=8, 1H), 7.06 (d, J=8, 1H),
7.11-7.20 (m, 2H), 7.40 (d, J=8, 1H), 7.49 (t, J=7, 1H), 7.88 (d,
J=8, 1H). .sup.13 C-NMR (CDCl3, .delta.): 39.8, 51.9, 58.8, 107.0,
110.9, 124.7, 126.4, 126.9, 128.5, 138.4. MS (%): 316 (parent+1,
100).
EXAMPLE 140
6-{4-[(2-Thiophen-2-yl-ethylamino)-methyl]-phenyl}-pyridin-2-ylamine
Prepared as in Example 135 in 68% yield as an amorphous solid
.sup.1 H-NMR (CDCl.sub.3, .delta.): 2.92 (t, J=6, 2H), 3.04 (t,
J=6, 2H), 3.84 (s, 2H), 4.48 (bs, 2H), 6.43 (d, J=8, 1H), 6.81-6.82
(m, 1H), 6.91-6.93 (m, 1H), 7.06 (d, J=8, 1H), 7.13 (m, 1H), 7.34
(d, J=8, 2H), 7.48 (t, J=7, 1H), 7.86 (d, J=8, 2H). .sup.13 C-NMR
(CDCl.sub.3, .delta.): 30.4, 50.3, 53.3, 106.9, 110.8, 123.5,
124.9, 126.8, 128.2, 138.3, 140.6, 142.9, 155.7, 158.2. MS (%): 310
(parent+1, 100).
EXAMPLE 141
6-[2-Methoxy-4-(phenethylamino-methyl)-phenyl]-pyridin-2-ylamine
Refer to Scheme 5
A. 2-Methoxy-4-methylphenylboronic acid:
To a 125 mL three-necked round-bottomed flask equipped with septum
and N.sub.2 inlet were added 2.3 g (11.4 mmol)
2-bromo-5-methylanisole (prepared as described in EP 470794 A1, see
Chem. Abs., 116:193935) and 25 mL dry tetrahydrofuran. The solution
was cooled to -70.degree. C., and 5.5 mL (13.7 mmol) of a 2.5 M
solution of butyl lithium in hexane added over 3 min. The reaction
was stirred 1 h at -70.degree. C., then 2.34 mL (13.7 mmol)
triethyl borate was added, and stirring continued for 2 h at
-70.degree. C. The reaction was warmed to room temperature and
stirred for 60 h, quenched with aqueous ammonium chloride solution
and dilute hydrochloric acid solution, and extracted with ethyl
acetate. The organic layer was washed with brine, dried over sodium
sulfate and evaporated to a dark oil, which was triturated with
hexane to afford 630 mg (33%) of an oil.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 2.37 (s, 3H), 3.89 (s, 3H),
6.715 (s, 1H), 6.84 (d, J=7, 1H), 7.70 (d, J=7, 1H).
B.
2-(2,5-Dimethylpyrrolyl)-6-(2-methoxy-4-methylphenyl)-pyridine:
Prepared as in Example 112A, using 953 mg (3.795 mmol)
2-(2,5-dimethyl)-6-bromopyridine, 630 mg (3.795 mmol)
2-methoxy-4-methylphenylboronic acid, 1.61 g (15.18 mmol) sodium
carbonate, 44 mg (0.038 mmol) tetrakis-triphenylphosphine
palladium, 18 mL ethanol, and 2 mL water, to give 670 mg (60%) of
an oil.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 2.28 (s, 6H), 2.45 (s, 3H),
3.93 (s, 3H), 5.98 (s, 2H), 6.87 (s, 1H), 6.94 (d, J=8, 1H), 7.14
(d, J=8, 1H), 7.84 (t, J=8, 1H), 7.91 (d, J=8, 1H), 7.98 (d, J=8,
1H). .sup.13 C-NMR (CDCl.sub.3, .delta.): 13.4, 21.7, 55.4, 106.7,
112.2, 119.2, 121.8, 123.1, 125.1, 128.6, 131.2, 137.6, 140.6,
151.3, 155.6, 157.1. APCI MS (%): 293 (parent+1, 100).
C. 6-(2-Methoxy-4-methylphenyl)-pyridin-2-ylamine:
Prepared as in Example 1F in 90% yield, as an oil.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 2.365 (s, 3H), 3.785 (s, 3H),
4.67 (bs, 2H), 6.34 (d, J=8, 1H), 6.76 (s, 1H), 6.84 (d, J=8, 1H),
7.09 (d, J=7.5, 1H), 7.39 (t, J=8, 1H), 7.57 (d, J=8, 1H). .sup.13
C-NMR (CDCl.sub.3, .delta.): 21.6, 55.4, 106.5, 112.15, 114.95,
121.5, 126.5, 130.6, 137.4, 139.5, 154.3, 156.7, 158.2. APCI MS
(%): 215 (parent+1, 100).
D. 2-Phthalimido-6-(2-methoxy-4-methylphenyl)-pyridine:
To a 100 mL round-bottomed flask eiquipped with condenser and
N.sub.2 inlet were added 440 mg (2.15 mmol)
6-(2-methoxy-4-methylphenyl)-pyridin-2-ylamine, 502 mg (2.29 mmol)
N-carbethoxyphthalimide, and 20 mL dry toluene. The solution was
refluxed 14 h, cooled, and purified by chromatography on silica gel
using hexane/ethyl acetate as eluant to afford 710 mg (90%) of a
low-melting solid.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 2.355 (s, 3H), 3.84 (s, 3H),
6.775 (s, 1H), 6.85 (d, J=8, 1H), 7.27 (m, 1H), 7.76 (m, 3H), 7.83
(t, J=8, 1H), 7.92 (m, 3H). .sup.13 C-NMR (CDCl.sub.3, .delta.):
21.3, 55.2, 112.0, 119.6, 121.6, 123.5, 124.7, 131.0, 131.5, 133.9,
134.4, 135.3, 137.8, 140.6, 156.0, 156.8, 166.8. APCI MS (%): 345
(parent+1, 100).
E. 2-Phthalimido-6-(2-methoxy-4-bromomethylphenyl)-pyridine:
To a 100 mL round-bottomed flask equipped with condenser and
N.sub.2 inlet were added 0.7 g (2.03 mmol)
2-phthalimido-6-(2-methoxy-4-methylphenyl)-pyridine, 0.36 g (2.03
mmol) N-bromosuccinimide, 10 mg azobisisobutyronitrile, and 30 mL
carbon tetrachloride. The reaction was heated at 50.degree. C. for
24 h, cooled, diluted with methylene chloride, and washed with
aqueous sodium bicarbonate solution, dried over magnesium sulfate,
and evaporated. The crude residue, 0.81 g, was used directly.
APCI MS (%): 423/425 (parent+1, 100).
F.
2-Phthalimido-6-[2-methoxy-4-(phenethylamino-methyl]phenyl)-pyridine:
To a 100 mL round-bottomed flask, equipped with condenser and
N.sub.2 inlet were added 120 mg (0.28 mmol)
2-phthalimido-6-(2-methoxy-4-bromomethylphenyl)-pyridine, 0.04 mL
(0.3 mmol) phenethylamine, 29 mg (0.35 mmol) sodium bicarbonate,
and 6 mL acetonitrile. The reaction wAas heated at 50.degree. C.
for 8 h, cooled, and extracted into ethyl acetate. The organic
layer was washed with brine, dried over magnesium sulfate, and
evaporated. The residue was chromatographed on silica gel using
methanol/methylene chloride to afford 40 mg (31%) of an oil.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 2.85 (m, 2H), 2.89 (m, 2H),
3.84 (s, 2H), 3.85 (s, 3H), 6.96 (m, 2H), 7.2-7.4 (m, 7H), 7.8-8.0
(m, 6H). APCI MS (%): 464 (parent+1, 100).
G.
6-[2-Methoxy-4-(phenethylamino-methyl)-phenyl]-pyridin-2-ylamine:
To a 100 mL round-bottomed flask equipped with condenser and
N.sub.2 inlet were added 30 mg (0.065 mmol)
2-phthalimide-6-[2-methoxy-4-(phenethylamino-methyl]phenyl)-pyridine,
7 uL (0.2 mmol) hydrazine, and 3 mL methanol. The reaction was
heated at 50.degree. C. for 3.5 h, cooled, arid concentrated. The
residue was dissolved in methylene chloride, washed with aqueous
sodium bicarbonate solution, dried over magnesium sulfate, and
evaporated. The residue was chromatographed on silica gel using
methanol/methylene chloride as eluant to afford 10 mg (46%) of an
oil, which was converted to the hydrochloride salt.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 2.88-2.95 (m, 4H), 3.82 (s,
3H), 3.87 (s, 2H), 6.43 (d, J=8, 1H), 6.94 (bs, 1H), 7.10 (d, J=8,
1H), 7.18-7.20 (m, 3H), 7.25-7.29 (m, 2H), 7.45 (t, J=8, 1H), 7.61
(d, J=8, 1H). MS(%): 334 (parent+1, 100).
EXAMPLE 142
6-{4-[(Cyclohexyl-methyl-amino)-methyl]-2-methoxy-phenyl}-pyridin-2-ylamine
Prepared as in Example 141, using N-methyl-cyclohexylamine, with an
86% yield in the final step.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 1.07-1.34 (m, 5H), 1.60-1.63
(m, 1H), 1.77-1.87 (m, 4H), 2.22 (s, 3H), 2.42-2.47 (m, 1H), 3.59
(s, 2H), 3.83 (s, 3H), 4.44 (bs, 2H), 6.41 (d, J=8, 1H), 7.95-7.98
(m, 2H), 7.13 (d, J=8, 1H), 7.44 (t, J=8, 1H), 7.59 (d, J=8, 1H).
.sup.13 C-NMR (CDCl.sub.3, .delta.): 26.0, 26.5, 28.6, 37.8, 55.7,
57.9, 62.0, 106.6, 111.6, 115.4, 121.3, 130.5, 137.5, 152.5, 157.0,
159.0. MS (%): 326 (parent+1, 100).
EXAMPLE 143
6-{4-[1-Cinnamyl-2-(4-isobutyl-piperazin-1-yl)-ethyl]-phenyl}-pyridin-2-yla
mine
Prepared as in Example 133 using cinnamyl bromide in the alkylation
analogous to Example 133A, in 98% yield for the final deblocking
step, converted to the hydrochloride salt in ether.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 0.85 (d, J=7, 6H), 1.73 (m,
J=6, 1H), 2.03 (d, J=7, 2H), 2.36 (m, 6H), 2.49 (m, 5H), 2.67 (m,
2H), 2.97 (m, 1H), 4.50 (bs, 2H), 6.08 (m, 1H), 6.30 (m, 1H), 6.39
(d, J=8, 1H), 7.04 (d, J=7, 1H), 7.12 (m, 1H), 7.21 (m, 7H), 7.45
(t, J=8, 1H), 7.82 (m, 2H). .sup.13 C-NMR (CDCl.sub.3, .delta.):
21.0, 25.3, 38.1, 43.7, 53.6, 64.1, 66.9, 106.9, 110.8, 126.0,
126.8, 128.1, 128., 128.8, 131.2, 137.7, 138.3, 144.8, 156.1,
158.2. APCI MS (%): 455 (parent+1, 100).
EXAMPLE 144
6-{4-[(Cyclohexyl-methyl-amino)-methyl]-2-fluoro-phenyl}-pyridin-2-ylamine
A. 2-Fluoro-4-methylphenylboronic Acid:
Prepared as in Example 141A, using 2-fluoro-4-methylbromobenzene,
in 97% yield, as a low-melting solid.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 2.37 (s, 3H), 6.86 (d, J=8,
1H), 7.00 (d, J=8, 1H), 7.685 (m, 1H).
B.
2-(2,5-Dimethylpyrrolyl)-3-(2-fluoro-4-methylphenyl)-pyridine:
Prepared as in Example 141B, in 73% yield as a low-melting, yellow
solid.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 2.20 (s, 6H), 2.37 (s, 3H),
5.91 (s, 2H), 6.97 (d, J=8, 1H), 7.04 (d, J=8, 1H), 7.13 (d, J=7,
1H), 7.84 (m, 2H), 7.98 (t, J=8, 1H). APCI MS (%): 281 (parent+1,
100).
C. 6-(2-Fluoro-4-methylphenyl)-pyridin-2-ylamine:
Prepared as in Example 141C in 68% yield, as an oil.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 2.35 (s, 3H), 6.43 (d, J=8,
1H), 6.92 (d, J=8, 1H), 7.01 (m, 1H), 7.09 (m, 1H), 7.46 (t, J=8,
1H), 7.76 (t, J=8, 1H). APCI MS (%): 203 (parent+1, 100).
D. 2-Phthalimido-6-(2-fluoro-4-methylphenyl)-pyridine:
Prepared as in Example 141D in 73% yield as a low-melting
solid.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 2.37 (s, 3H), 6.96 (d, J=8,
1H), 7.04 (m, 1H), 7.35 (dd, J=1,8, 1H), 7.8-8.0 (m, 7H). APCI MS
(%): 333 (parent+1, 100).
E. 2-Phthalimido-6-(2-fluoro)-4-bromomethylphenyl)-pyridine:
Prepared as in Example 141E in 62% yield as a crude solid, which
was used directly in the following step.
APCI MS (%): 411/413 (parent+1, 45/42), remianing peaks due to
impurities.
F.
2-Phthalimido-6-[2-fluoro-4-(N-cyclohexyl-N-methylamino-methyl]phenyl)-pyr
idine:
Prepared as in Example 141F in 8% yield as an oil.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 1.22 (m, 6H), 1.6-1.8 (m, 4H),
2.22 (s, 3H), 2.45 (m, 1H), 3.62 (s, 2H), 7.19 (d, J=7, 1H), 7.35
(dd, J=1,8, 1H), 7.8-8.0 (m, 8H). APCI MS (%): 444 (parent+1,
100).
G.
6-{4-[(Cyclohexyl-methyl-amino)-methyl]-2-fluoro-phenyl}-pyridin-2-ylamine
:
Prepared as in Example 141G in 57% yield as an oil, which was
converted to the hydrochloride salt.
.sup.1 H-NMR (hydrochloride sail: in CD.sub.3 OD, .delta.):
1.16-1.48 (m, 7H), 1.57-1.77 (m, 3H), 1.89-2.05 (m, 2H), 2.09-2.22
(m, 2H), 2.76 (s, 2H), 7.05 (d, J=8, 1H), 7.16 (s, J=8, 1H),
7.58-7.66 (m, 2H), 7.83 (t, J=8, 1H), 7.99 (t, J=8, 1H). APCI
MS(%): 314 (parent+1, 100).
EXAMPLE 145
6-[4-((N-Phenethyl-N-methylamino-methyl)-phenyl]-pyridin-2-ylamine
Prepared as in Example 133D in 57% yield, mp>250.degree. C., as
the hydrochloride salt.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 2.30 (s, 3H), 2.67 (m, 2H),
2.83 (m, 2H), 3.60 (s, 2H), 4.51 (bs, 2H), 6.43 (d, J=8, 1H), 7.08
(d, J=7, 1H), 7.19 (m, 3H), 7.25 (m, 2H), 7.35 (m, 2H), 7.48 (t,
J=8, 1H), 7.87 (m, 2H). .sup.13 C-NMR (CD.sub.3 OD, .delta.) 33.8,
42.2, 59.1, 61.85, 107.0, 110.7, 125.9, 126.7, 128.3, 128.7, 129.2,
138.3, 138.4, 139.3, 140.4, 156.0, 158.3. MS (%): 318 (parent+1,
100).
EXAMPLE 146
6-{4-[2-(4-(Isoquinolin-1-yl)-piperazin-1-yl)-ethyl]-phenyl}-pyridin-2-ylam
ine
Prepared as in Example 1, using N-isoquinolin-1-yl-piperazine, in
30% yield.
.sup.1 H-NMR (CDCl.sub.3, .delta.): 2.63 (m, 2H), 2.75 (bs, 4H),
2.85 (m, 2H), 3.38 (bs, 4H), 5.95 (bs, 2H), 6.39 (d, J=8, 1H), 7.02
(d, J=7, 1H), 7.31 (m, 2H), 7.39 (d, J=4, 1H), 7.45 (t, J=8, 1H),
7.60 (t, J=6, 1H), 7.71 (t, J=6, 1H), 7.89 (m, 3H), 8.09 (m, 2H).
MS (%): 410 (parent+1, 100), 216 (38), 145 (45). Anal. (after
conversion to the hydrochloride salt) Calc'd. for C.sub.26 H.sub.27
N.sub.5.4HCl.2H.sub.2 O: C, 52.79, H, 5.92, N, 11.83. Found: C,
53.11, H, 6.06, N, 11.53.
* * * * *